AU2006228435A1 - New class of gammadelta T cells activators and use thereof - Google Patents

Description

WO 2006/103568 PCT/IB2006/001206 1 NEW CLASS OF y8 T CELLS ACTIVATORS AND USE THEREOF FIELD OF THE INVENTION 5 The present invention relates to a new class of compounds having y8 T cells activating properties referred to herein as angelyl phosphoesters, compositions comprising any of these compounds and methods for regulating an immune response in a subject comprising the step of administering these compounds. 10 BACKGROUND Most human peripheral blood y8 T cells express a y'TCR heterodimer encoded by Vy9/VN82 genes, some NK-lineage receptors for MHC class I and almost no CD4 nor CD8. These cells have been shown to exhibit strong, non MHC-restricted, cytolytic activity against virus-infected cells (Poccia et al (1997), parasite-infected cells (Constant et al (1995)), or tumor cells (Fournie et Bonneville 15 (1996)). These cells are also physiologically amplified in the context of several unrelated infectious diseases such as tuberculosis, malaria, tularemia, colibacillosis and also by B-cell tumors (for review see Hayday, 2000). Beside their anti-infectious activity, it was shown in short term cytotoxicity assays that Vy9N82 T 20 cells are able to lyse a wide variety of tumor cell lines from very diverse origins : lymphoma and leukemia from B-cell, T-cell or myeloid lineages (Fisch et al., 2000; Selin et al., 1992; Sicard et al., 2001; Sturm et al., 1990; Zheng et al., 2001a), breast carcinoma (Bank et al., 1993), glioblastoma (Fujimiya et al., 1997; Yamaguchi et al., 1997), renal cell carcinoma (Choudhary et al., 1995; Kobayashi et al., 2001; Mitropoulos et al., 1994), nasopharyngeal carcinoma (Zheng et al., 2001b), 25 lung adenocarcinoma (Ferrarini et al., 1996). In microbes, Vy9/VN82 + lymphocytes spontaneously recognize a structurally related set of nonpeptide antigens, referred to as natural phosphoantigens and alkylamines. In B cell tumors, the nature of antigens for the y8 T cells remains unidentified. Vy9VN82 + lymphocytes are also 30 responsive to a variety of virally infected-, activated- or tumoral cell types without prior exposure. Again, in these situations, the responsible antigens remain unknown (for review see Fisch, 2000). It has been shown that, in vitro, Vy9/V82 2 + lymphocytes respond to synthetic drugs such as therapeutic aminobisphosphonates (reviewed in Espinosa, 2001), leading to their in vitro activation. Recognition of natural non-peptide antigens is mediated by the y8 TCR, through amino acid 35 residues located on both V'9- and V82- CDR3 regions. Although neither processing nor WO 2006/103568 PCT/IB2006/001206 2 presentation by CD1 or MHC molecules is involved, Vy9/V82 + lymphocyte activation by non peptide antigens appears to require cell-to-cell contact (Lang, 1995; Morita, 1995; Miyagawa, 2001, Rojas, 2002). 5 The stimulating bacterial antigens have been shown to be small non peptidic compounds classically referred to as phosphoantigens (Behr et al., 1996; Belmant et al., 2000; Constant et al., 1995; Poquet et al., 1998; Tanaka et al., 1995), owing to the presence of phosphate groups in most instances. 10 Vy9N82 T cells can also be activated through endogenous metabolites (acting in the micromolar range) such as isopentenyl pyrophosphate or IPP (Espinosa et al., 2001b; Tanaka et al., 1995), which is produced through the conventional mevalonate pathway shared by both microorganisms and mammalian cells. Production of IPP in the latter cells can be up-regulated in situations of cell stress and transformation. In particular a recent study has reported a correlation between the 15 endogenous production levels of IPP in tumor cells and their susceptibility to Vy9/VN82 T cell mediated lysis (Gober et al., 2003). Also consistent with a direct contribution of endogenous metabolites of the mevalonate pathway to Vy9NV82 T cell recognition, cell treatment with pharmacological agents preventing IPP 20 biosynthesis (such as statins) or leading to IPP accumulation (such as aminobisphosphonates, see below) lead respectively to decreased or enhanced Vy9NV82 T cell stimulating properties of the treated cells (Gober et al., 2003; Kato et al., 2001). Aminobisphosphonates are thought to inhibit FPP synthase, an enzyme in the mevalonate pathway, 25 the inhibition of which causes the accumulation and release of upstream isoprenoid lipids such as IPP. Aminobisphosphonate compounds had been used in human therapy for the treatment of bone metastases in cancer patients, and provided a first set of evidence for in vivo expansion of human V9/V9N82 + lymphocytes induced by phosphoantigen agonists, reporting increases of circulating 'y8 T cells within one to three weeks in human adults with multiple myeloma after therapeutic 30 intravenous injection of 60-90 mg of pamidronate (Kunzmann et al, 1999). However, such compounds require presentation by antigen presenting cells and cannot produce substantial stimulation of Vy9/V82 T cell activity as assessed by cytokine secretion in a pure Vy9/VN82 T cell culture. Moreover, pamidronate shows very low potency of activation of y8 T cells, reported to achieve at best only 2-fold increase in y8 T cell count (Wilhelm et al., 2003). 35 WO 2006/103568 PCT/IB2006/001206 3 Recently, several highly potent 78 T cell activating pyrophosphate-containing compounds have been described which directly activate 78 T cells. In particular, phosphohalohydrin and phosphoepoxide compounds were described by the group of J.J. Fournie. (R, S)-3-(bromomethyl) 3-butanol-l-yl-diphosphate, also referred to as BrHPP (BromoHydrin PyroPhosphate) is currently 5 used in ongoing human clinical studies to stimulate the proliferation of y8 T cells ex vivo. Other pyrophosphate containing compounds with high specific activity (EC50 in the nanomolar or better range) are produced through an isoprenoid biosynthetic pathway called the 'Rohmer" or "non mevalonate" pathway, which is specific to pro- and eukaryotic microorganisms (Feurle et al., 2002; Hintz et al (2003); Jomaa et al., 1999a; Jomaa et al., 1999b; Rohmer et al., 1993). 10 Despite the foregoing, there is still a need of new compounds providing y8 T cell activation, in particular compounds having increased potency and/or preferred pharmacodynamic properties. Such compounds have particular advantages in non-life threatening or chronic therapeutic indications where therapies should be free of toxicity. 15 SUMMARY OF THE INVENTION The present invention now discloses a new class of compounds having y8 T cell activating properties. This new class of compounds is referred to as the angelyl and tiglyl phosphoester class. The inventors have found that the class of compounds described herein have high potency in 20 comparison to other compounds known to modulate y8 T cell activity. Preferably the compounds of the invention are isolated, purified or partially purified. These compounds can be used to efficiently regulate the activity of y8 T cells, particularly the activation and proliferation of y8 T cells, preferably Vy9/V82 T cells, in vivo in a subject. These 25 new y8 T cell activators can be used in accordance with any of the methods described herein. These compounds are particularly suited for immunotherapy, particularly to treat a subject having a tumor or a subject suffering from other diseases, particularly an infectious disease, an autoimmune disease or an allergic disease. Compounds according to the present invention can also be used as a vaccine adjuvant. 30 Accordingly, the invention provides a y8 T cell activator of formula (I):

R

3 0 0

R

5 -W= C--A- -P-B- -P-Y I I I C I

K

7 N -at i O-Cat + -m() WO 2006/103568 PCT/IB2006/001206 4 wherein Cat+ represents one (or several, identical or different) organic or mineral cation(s) (including proton); m is an integer from 1 to 3; B is O, NH, or any other group capable of being hydrolyzed; 5 A is O, NH, CHF, CF 2 or CH 2 , or any other isosteric group; W is C-R 6 or N;

R

7 is a (CI-C 3 )alkyl group or any other isosteric group such as CF 3 ;

R

3 , R 4 and R 6 , identical or different, are a hydrogen or a (C 1

-C

3 )alkyl group or any other isosteric group such as CF3; 10 R 5 is an (C 2

-C

3 )acyl, an aldehyde, an (C 1

-C

3 )aleohol, or an (C 2

-C

3 )ester; and, Y = O'Cat+, a (CI-C 3 ) alkyl group, a group -A-R, wherein R is a linear, branched, or cyclic, aromatic or not, saturated or unsaturated, C-Cs 50 hydrocarbon group, optionally interrupted by at least one heteroatom, wherein said hydrocarbon group comprises an alkyl, an alkylenyl, or an alkynyl, preferably an alkyl or an alkylene, which can be substituted by one or several substituents 15 selected from the group consisting of: an alkyl, an alkylenyl, an alkynyl, an epoxyalkyl, an aryl, an heterocycle, an alkoxy, an acyl, an alcohol, a carboxylic group (-COOH), an ester, an amine, an amino group (-NH 2 ), an amide (-CONH 2 ), an imine, a nitrile, an hydroxyl (-OH), an aldehyde group (-CHO), an halogen, an halogenoalkyl, a thiol (-SH), a thioalkyl, a sulfone, a sulfoxide, and a combination thereof. 20 Preferably, A is O or CH 2 . More preferably, A is O. More preferably, R 3 , R 4 and R 6 are a hydrogen. Preferably, R 5 is -CH 2 -OH, -CHO, -CO-CH 3 or -CO-OCH 3 . More preferably, R 5 is -CH 2 -OH. Preferably, R 7 is CH 3 or an isosteric group thereof, such as CH 2 F, CF 2 H or CF 3 . Preferably, m is 1. 25 In one embodiment, the group R 5 and the moiety -CR 3

R

4 -A-[POOB]m-POOY of formula (I) are in Z (or cis) configuration. In another embodiment, the group R 5 and the moiety -CR 3 R4-A-[POOB]m POOY of formula (I) are in E (or trans) configuration with respect to the double bond position. Insofar as it is observed herein (see Examples) that 78 T cell activator of formula (I) in which the group R5 and the moiety -CR 3

R

4 -A-[POOB]m-POOY are in Z configuration has significantly 30 greater activity in the activation of y8 T cells than the E configuration, the Z configuration is preferred. In one aspect, said activator is a compound selected from the group consisting of: 35 WO 2006/103568 PCT/IB2006/001206 5 A compound of Fomula (II): R6 R3 O O R5I I I R5 ,C--- -C- -- P-B- P-Y R7 R4 O-Cat+ O-Cat+ (II) wherein Cat+, m, B, A, Rs, R3, R 4 , R 6 , R7, and Y are defined as in Formula (I). 5 A compound of Fomula (UI): R3 O O I 11 i1 R5-N= -C-A- -P-B--P-Y I I I I R7 R4 O-Cat+ O-Cat+ m (III) wherein Cat+, m, B, A, Rs, R3, R 4 , R7, and Y are defined as in Formula (I). A compound of Fomula (IV): R3 O O HOCH-W=C-C-A--P-B -- P -Y I I I I R7 R4 O-Cat+ O-Cat+ m 10 (IV) wherein Cat+, m, B, A, W, R5, R3, R 4 , R 6 , R7, and Y are defined as in Formula (I). A compound of Fomula (V): R3 O O I ft ft R5-W=C-C-A--P-B -P-Y I I I I CH3 R4 O-Cat+ O-Cat+ -5 -m (V) 15 wherein Cat+, m, B, A, W, Rs, 13, R 4 , R 6 , and Y are defined as in Formula (I).

WO 2006/103568 PCT/IB2006/001206 6 A compound of Fomula (VI): R3 0 0 HOCH--WC-C-A- -P-B--P-Y I I II II CH3 R4 O-Cat+ O-Cat+ m (VI) wherein Cat+, m, B, A, W, R 3 , R 4 , R 6 , and Y are defined as in Formula (I). 5 A compound of Fomula (VII): R3 R8 O O R5 - W C- Ij' R5-W=C-C-C- -P-B- -P-Y I I I I I R7 R4 R9 O-Cat+ O-Cat+ m (VII) wherein Cat+, m, B, W, Rs, R3, R 4 , R 6 , RT, and Y are defined as in Formula (I), R 8 is H or F, and R 9 is H or F. 10 A compound of Formula (VIII): R3 O O R5-W---C-N- -P-B -P-Y I I H I I R7 R4 O-Cat+ O-Cat+ m (VIII) wherein Cat+, m, B, W, Rs, R3, R 4 , R 6 , R7, and Y are defined as in Formula (I). A compound of Formula (IX): R3 O O I P HCH-WC-C -- P-B--P-Y CH R4 O-Cat+ O-Cat+ 15 m (IX) wherein Cat+, m, B, W, 13, R 4 , R 6 , and Y are defined as in Formula (I).

WO 2006/103568 PCT/IB2006/001206 7 A compound of Formula (X): R3 R8 0 O HOCHW=C-C- C--P-B- -pI-Y I I I I I

CH

3 R4 R9 O-Cat+ O-Cat+ - -m (X) wherein Cat+, m, B, W, R3, R 4 , R6, and Y are defined as in Formula (I), R 8 is H or F, and R9 is H or F. 5 A compound of formula (XI): R3 O O 1 11 111 HOCH--W=C-C N- P-B P-Y I I H I I CH3 R4 O-Cat+ O-Cat+ - -m m (XI) wherein Cat+, m, B, W, R3, R 4 , R6, and Y are defined as in Formula (I). 10 In a preferred embodiments, the y8 T cell activator is a compound of formula (XII) or (XII'): OH 0 0 O-P-O-P-O'Cat* /I I+ O-Cat+ O-Cat+ (XII) (Z)-4-hydroxy-2-methylbut-2-enyl pyrophosphate (also referred to as HIAngelylPP) O 0 HO 1i II HOO-P-0--O-Cat* I I O-Cat+ O-Cat+ (XIP) 15 (E)-4-hydroxy-2-methylbut-2-enyl pyrophosphate (also referred to as HTiglylPP) 20 WO 2006/103568 PCT/IB2006/001206 8 In further preferred embodiments, the y8 T cell activator is a compound of formula (XIII) or (XII'): OH II P-O-P-O-Cat* I I O-Cat* O-Cat* (XIII) (Z)-5-hydroxy-3-methylpent-3-enyl pyrophosphonate (also referred to as C-HAngelylPP) 5 00 OHOO HO~ P-0-P- -OCat O-Catv O-Cat (XIHI) (E)-5-hydroxy-3-methylpent-3-enyl pyrophosphonate (also referred to as C-HTiglylPP) In additional preferred embodiments, the y8 T cell activator is a compound of formula (XIV) or 10 (XIV'): OH O 0 III N-P-O-P-O-Cat* H I + I O'Cat O-Cat' (XIV) (Z)-4-hydroxy-2-methylbut-2-enyl pyrophosphoramidate (also referred to as N-HAngelylPP) O O HO II II H - N-P-0-P O-Cat* H I I O-Cat+ O-Cat+ (XIV') 15 (E)-4-hydroxy-2-methylbut-2-enyl pyrophosphoramidate (also referred to as N-HTiglylPP) 20 WO 2006/103568 PCT/IB2006/001206 9 In further embodiments, the y8 T cell activator is a compound of formula (XV): 0 z O NH OH O 0 0 II II II I I I I I (r--A-P-O-P-O-P-O 0 O-Cat O-Cat + O-Cat+ H H H] H OH X (XV) wherein Cat+ and A are defined as in Formula (I); X is H and Z is CH 3 (deoxyribonucleoside is thymydine) or X is OH and Z is H (ribonucleoside is uridine). In one embodiment, the compound 5 of formula (XVI) is in E (or trans) configuration. In a preferred embodiment, the compound of formula (XVI) is in Z (or cis) configuration. The present invention also provides pharmaceutical composition comprising a y8 T cell activator according to any one of the embodiments described herein. In preferred embodiments, the Cat+ 10 cation will be a pharmaceutically acceptable cation. Also provided are methods of modulating, preferably activating, a y8 T cell, the method comprising bringing a y8 T cell into contact with a y8 T cell activating compound described herein. As will be appreciated, compounds of the invention may be used to activate y8 T cell in vitro or in vivo. y8 T cells activated in vitro may be used in any suitable method following activation, including in therapy or prevention of disease. In 15 one preferred example, activated y8 T cells are administered to a mammal, preferably a human. In a preferred aspect, the invention encompasses a method of treatment comprising (a) bringing a y8 T cell into contact with a y8 T cell activating compound described herein and (b) administering y8 T cells of step (a) to a subject. Methods for preparing y8 T cells for such applications are known in the art, for example can be carried out as described in US2005196385 and W003070921, both 20 by Romagne and Laplace, the disclosures of which are incorporated herein by reference. Also provided are methods of modulating, preferably activating, a y8 T cell comprising administering to a subject a y8 T cell activator described herein. In preferred embodiments, the inventions provides a method for treating or preventing a disease comprising administering to a 25 subject a y8 T cell activator described herein in an amount sufficient to ameliorate or prevent said disease. Also provided is the use of a y8 T cell activator of the invention for the manufacture of a pharmaceutical composition for regulating y8 T cells in a human subject, preferably thereby WO 2006/103568 PCT/IB2006/001206 10 treating a disease. Preferably said disease is a tumor or proliferative disorder, an infectious disease, an autoimmune disease or an allergic disease. Additional embodiments and details are futher provided herein. 5 DESCRIPTION OF THE DRAWINGS Figure 1 is a synthetic scheme for the preparation of compound HTiglylPP as carried out in Example 1. 10 Figure 2 is a synthetic scheme for the preparation of compounds H-AngelylPP and C-HAngelylPP as carried out in Examples 2 and 3. Figure 3 shows an in vitro dose reponse curve and EC50 values for compounds of the invention 15 HAngelylPP and HTiglylPP, and reference compounds (R,S)-BrHPP and (E)-HDMAPP. DETAILED DESCRIPTION Definitions Within the context of the present invention, the expression "regulating the activity of y8 T cells" 20 designates causing or favoring an increase in the number and/or biological activity of such cells in a subject. Regulating thus includes without limitation modulating (e.g., stimulating) expansion of such cells in a subject and/or, for instance, triggering of cytokine secretion (e.g., TNFx or IFNy). As indicated, y8 T cells normally represent between about 1-10% of total circulating lymphocytes in a healthy adult human subject. The present invention can be used to significantly increase the y8 25 T cells population in a subject, particularly to reach at least 10%, 12%, 15%, 20%, or 30-90% of total circulating lymphocytes, typically 40-90%, more preferably from 50-90%. In typical embodiments, the invention allows the selective expansion of y8 T cells in a subject, to reach 60 90% of total circulating lymphocytes, preferably 70-90%, more preferably from 80-90%. Regulating also includes, in addition or in the alternative, modulating the biological activity of y8 T 30 cells in a subject, particularly their cytolytic activity or their cytokine-secretion activity. The invention defines novel conditions and strategies for increasing the biological activity of y8 T cells towards target cells. Where "comprising" is used, this can preferably be replaced by "consisting essentially of", more 35 preferably by "consisting of".

WO 2006/103568 PCT/IB2006/001206 11 Where hereinbefore and hereinafter numerical terms are used, they are meant to include the numbers representing the upper and lower limits. For example, "between 1 and 3" stands for a range "from and including 1 up to and including 3", and "in the range from 1 to 3" would stand for "from and including 1 up to and including 3". The same is true where instead of numbers (e.g. 3) 5 words denoting numbers are used (e.g. "three"). Where "about" is used in connection with a number, this preferably means the number +/-15%, more preferably the number plus 5%, most preferably the number itself without "about". For example, "about 100" would stand for "from and including 85 to and including 115". Where 10 "about" is used in connection with numeric ranges, for example "about 1 to about 3", or "between about one and about three", preferably the definition of "about" given for a number in the last sentence is applied to each number defining the start and the end of a range separately. Preferably, where "about" is used in connection with any numerical values, the "about" can be deleted. 15 "Weekly" stands for "about once a week" (meaning that more than one treatment is made with an interval of about one week between treatments), the about here preferably meaning +/-1 day (that is, translating into "every 6 to 8 days"); most preferably, "weekly" stands for "once every 7 days". As used herein, the term "EC50" with respect to regulating the activity of y8 T cells, refers to the 20 efficient concentration of the subject compositions which produces 50% of its maximum response or effect with respect to such activity of 78 T cells. The term "isolated" refers to a compound or product that is refers to a compound which represents at least 30%, more preferably at least 50%, 60% or 70%, and most preferably at least 80%, 90%, 25 95% or 98% of the compound present in the mixture. "Purified" phosphoantigen or phosphoantigen composition refers to substantially pure phosphoantigen, essentially pure phosphoantigen, or a salt thereof, or to phosphoantigen, or a salt thereof which is substantially free, essentially free, or free of another compound. 30 "Partially purified" phosphoantigen or phosphoantigen composition refers to phosphoantigen, or a salt thereof that is less than 90% pure. New class of y;S T lymphocyte activators: Angelyl and tiglyl phosphoesters 35 The new class of compounds described by the present inventors comprises angelyl and tiglyl phosphoesters. The inventors have found that the compounds of this class show significant WO 2006/103568 PCT/IB2006/001206 12 potency over other compounds in modulating y8 T cell activity. The recognition of the angelyl phosphoester compounds by their biological target may involve an enzymatic processing of the compound. This processing is thought to rely on an intramolecular cyclization reaction concerted with the hydrolysis of the labile phosphate moiety (or energy release). The angelyl phosphoester 5 compounds in Z isomer are predicted to favor the intramolecular cyclization, compared to the tiglyl phosphoester E isomer. Compounds of the angelyl phosphoester class may have increased potency (e.g. less compound needed, less likelihood of toxicity), or these compositions can provide distinct pharmacological properties, for example target binding affinity, ADME properties (absorption, distribution, metabolism and excretion) over previously known activators of y8 T cells. In further 10 preferred embodiments, specific compounds of the invention are provided which may each have differing properties and can be used depending on the application sought. For example the compounds may differ as to in vivo stability, leading for example to different circulation half-lives or different maximal activation of y8 T cells. 15 The new class of y8 T lymphocyte activators according to the present invention comprises the compounds of formula (I):

R

3 0 0 I || ||

R

5 -W= -C-A- -P-B--P-Y I I II I

R

7

R

4 O-Cat O-Cat + - m (I) wherein Cat+ represents one (or several, identical or different) organic or mineral cation(s) (including proton); 20 m is an integer from 1 to 3; B is O, NH, or any other group capable of being hydrolyzed; A is O, NH, CHF, CF 2 or CH 2 , or any other isosteric group; W is C-R 6 or N;

R

7 is a (CI-C 3 )alkyl group or any other isosteric group such as CF 3 ; 25 R 3 , R 4 , and R 6 , identical or different, are a hydrogen or a (CI-C 3 )alkyl group or any other isosteric group such as CF 3 ;

R

5 is an (C 2

-C

3 )acyl, an aldehyde, an (Cl-C 3 )alcohol, or an (C 2

-C

3 )ester; and, Y = O-Cat+, a CI-C 3 alkyl group, a group -A-R, wherein R is a linear, branched, or cyclic, aromatic or not, saturated or unsaturated, CI-C 50 hydrocarbon group, optionally interrupted by at 30 least one heteroatom, wherein said hydrocarbon group comprises an alkyl, an alkylenyl, or an alkynyl, preferably an alkyl or an alkylene, which can be substituted by one or several substituents selected from the group consisting of: an alkyl, an alkylenyl, an alkynyl, an epoxyalkyl, an aryl, an WO 2006/103568 PCT/IB2006/001206 13 heterocycle, an alkoxy, an acyl, an alcohol, a carboxylic group (-COOH), an ester, an amine, an amino group (-NH 2 ), an amide (-CONH 2 ), an imine, a nitrile, an hydroxyl (-OH), a aldehyde group (-CHO), an halogen, an halogenoalkyl, a thiol (-SH), a thioalkyl, a sulfone, a sulfoxide, and a combination thereof. 5 An "isosteric group" refers to to elements, functional groups, substitutents, molecules or ions having different molecular formulae but exhibiting similar or identical physical properties. For example, CF 3 is an isosteric group of CH3. Typically, two isosteric groups have similar or identical volumes and shapes. 10 In a particular embodiment, Y can be a radical selected from the group consisting of a nucleoside, a nucleotide, an oligonucleotide, a nucleic acid, an amino acid, a peptide, a protein, a monosaccharide, an oligosaccharide, a polysaccharide, a fatty acid, a simple lipid, a complex lipid, a folic acid, a tetrahydrofolic acid, a phosphoric acid, an inositol, a vitamin, a co-enzyme, a 15 flavonoid, an aldehyde, an epoxide and a halohydrin. In one embodiment, the group R 5 and the moiety -CR 3

R

4 -A-[POOB]m-POOY of formula (I) are in Z (or cis) configuration. In another embodiment, the group Rs and the moiety -CR 3

R

4 -A-[POOB]m POOY of formula (I) are in E (or trans) configuration. Insofar as it is observed herein (see 20 Examples) that 78 T cell activator of formula (I) in which the group Rs and the moiety -CR 3

R

4

-A

[POOB]m-POOY are in Z configuration has significantly greater activity in the activation of y5 T cells than the E configuration, the Z configuration is preferred. In a particular embodiment, the substituents as defined above are substituted by at least one of the 25 substituents as specified above. Preferably, the substituents are selected from the group consisting of : an (C 1

-C

6 )alkyl, an (C 2 C 6 )alkylenyl, an (C 2

-C

6 )alkynyl, an (C 2

-C

6 )epoxyalkyl, an aryl, an heterocycle, an (C 1

-C

6 )alkoxy, an (C 2

-C

6 )acyl, an (Ca-C 6 )alcohol, a carboxylic group (-COOH), an (C 2

-C

6 )ester, an (C 1

-C

6 )amine, 30 an amino group (-NHi 2 ), an amide (-CONH 2 ), an (C1-C 6 )imine, a nitrile, an hydroxyl (-OH), a aldehyde group (-CHO), an halogen, an (C 1

-C

6 )halogenoalkyl, a thiol (-SH), a (C 1

-C

6 )thioalkyl, a (Ci-C 6 )sulfone, a (C 1

-C

6 )sulfoxide, and a combination thereof. More preferably, the substituents are selected from the group consisting of : an (C 1

-C

6 )alkyl, an 35 (C 2

-C

6 )epoxyalkyl, an (C 2

-C

6 )alkylenyl, an (C 1

-C

6 )alkoxy, an (C 2

-C

6 )acyl, an (Ci-C 6 )alcohol, an

(C

2

-C

6 )ester, an (CI-C 6 )amine, an (C 1

-C

6 )imine, an hydroxyl, a aldehyde group, an halogen, an (C 1 C 6 )halogenoalkyl, and a combination thereof.

WO 2006/103568 PCT/IB2006/001206 14 Still more preferably, the substituents are selected from the group consisting of : an (C 3 C 6 )epoxyalkyl, an (C1-C3)alkoxy, an (C 2

-C

3 )acyl, an (C 1

-C

3 )alcohol, an (C 2

-C

3 )ester, an (Cl

C

3 )amine, an (C 1

-C

3 )imine, an hydroxyl, an halogen, an (Cz-C 3 )halogenoalkyl, and a combination 5 thereof. Preferably, said hydrocarbon group is a (C 3

-C

25 )hydrocarbon group, more preferably a (Cs Clo)hydrocarbon group. 10 In the context of the present invention, the term "alkyl" more specifically means a group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl and the other isomeric forms thereof. (Ci-C 6 )alkyl more specifically means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the 15 other isomeric forms thereof. (CI-C 3 )alkyl more specifically means methyl, ethyl, propyl, or isopropyl. The term "alkenyl" refers to an alkyl group defined hereinabove having at least one unsaturated ethylene bond and the term "alkynyl" refers to an alkyl group defined hereinabove having at least 20 one unsaturated acetylene bond. (C 2

-C

6 )alkylene includes a ethenyl, a propenyl (1-propenyl or 2 propenyl), a 1- or 2- methylpropenyl, a butenyl (1-butenyl, 2-butenyl, or 3-butenyl), a methylbutenyl, a 2-ethylpropenyl, a pentenyl (1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl), an hexenyl (1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl), and the other isomeric forms thereof. (C 2

-C

6 )alkynyl includes ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 25 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, or 5 hexynyl and the other isomeric forms thereof. The term "epoxyalkyl" refers to an alkyl group defined hereinabove having an epoxide group. More particularly, (C 2

-C

6 )epoxyalkyl includes epoxyethyl, epoxypropyl, epoxybutyl, epoxypentyl, 30 epoxyhexyl and the other isomeric forms thereof. (C 2

-C

3 )epoxyalkyl includes epoxyethyl and epoxypropyl. The "aryl" groups are mono-, bi- or tri-cyclic aromatic hydrocarbons having from 6 to 18 carbon atoms. Examples include a phenyl, o-naphthyl, 13-naphthyl or anthracenyl group, in particular. 35 "Heterocycle" groups are groups containing 5 to 18 rings comprising one or more heteroatoms, preferably 1 to 5 endocyclic heteroatoms. They may be mono-, bi- or tri-cyclic. They may be WO 2006/103568 PCT/IB2006/001206 15 aromatic or not. Preferably, and more specifically for Rs, they are aromatic heterocycles. Examples of aromatic heterocycles include pyridine, pyridazine, pyrimidine, pyrazine, furan, thiophene, pyrrole, oxazole, thiazole, isothiazole, imidazole, pyrazole, oxadiazole, triazole, thiadiazole and triazine groups. Examples of bicycles include in particular quinoline, isoquinoline and quinazoline 5 groups (for two 6-membered rings) and indole, benzimidazole, benzoxazole, benzothiazole and indazole (for a 6-membered ring and a 5-membered ring). Nonaromatic heterocycles comprise in particular piperazine, piperidine, etc. "Alkoxy" groups correspond to the alkyl groups defined hereinabove bonded to the molecule by an 10 -0- (ether) bond. (Ci-C 6 )alkoxy includes methoxy, ethoxy, propyloxy, butyloxy, pentyloxy, hexyloxy and the other isomeric forms thereof. (Ci-C 3 )alkoxy includes methoxy, ethoxy, propyloxy, and isopropyloxy. "Alcyl" groups correspond to the alkyl groups defined hereinabove bonded to the molecule by an 15 CO- (carbonyl) group. (C 2

-C

6 )acyl includes acetyl, propylacyl, butylacyl, pentylacyl, hexylacyl and the other isomeric forms thereof. (C 2

-C

3 )acyl includes acetyl, propylacyl and isopropylacyl. "Alcohol" groups correspond to the alkyl groups defined hereinabove containing at least one hydroxyl group. Alcohol can be primary, secondary or tertiary. (CI-C 6 )alcohol includes methanol, 20 ethanol, propanol, butanol, pentanol, hexanol and the other isomeric forms thereof. (CI-C 3 )alcohol includes methanol, ethanol, propanol and isopropanol. "Ester" groups correspond to the alkyl groups defined hereinabove bonded to the molecule by an COO- (ester) bond. (C 2

-C

6 )ester includes methylester, ethylester, propylester, butylester, 25 pentylester and the other isomeric forms thereof. (C 2

-C

3 )ester includes methylester and ethylester. "Amine" groups correspond to the alkyl groups defined hereinabove bonded to the molecule by an -N- (amine) bond. (CI-C 6 )amine includes methylamine, ethylamine, propylamine, butylamine, pentylamine, hexylamine and the other isomeric forms thereof. (C-C 3 )amine includes 30 methylamine, ethylamine, and propylamine. "Imine" groups correspond to the alkyl groups defined hereinabove having a (-C=N-) bond. (C 1 C 6 )imine includes methylimine, ethylimine, propylimine, butylimine, pentylimine, hexylimine and the other isomeric forms thereof. (C 1

-C

3 )imine includes methylimine, ethylimine, and propylimine. 35 The halogen can be Cl, Br, I, or F, more preferably Br or F.

WO 2006/103568 PCT/IB2006/001206 16 "Halogenoalkyl" groups correspond to the alkyl groups defined hereinabove having at least one halogen. The groups can be monohalogenated or polyhalogenated containing the same or different halogen atoms. For example, the group can be an trifluoroalkyl (CF 3 -R). (CI-C 6 )halogenoalkyl includes halogenomethyl, halogenoethyl, halogenopropyl, halogenobutyl, halogenopentyl, 5 halogenohexyl and the other isomeric forms thereof. (C 1

-C

3 )halogenoalkyl includes halogenomethyl, halogenoethyl, and halogenopropyl. "Thioalkyl" groups correspond to the alkyl groups defined hereinabove bonded to the molecule by an -S- (thioether) bond. (Ci-C 6 )thioalkyl includes thiomethyl, thioethyl, thiopropyl, thiobutyl, 10 thiopentyl, thiohexyl and the other isomeric forms thereof. (CI-C 3 )thioalkyl includes thiomethyl, thioethyl, and thiopropyl. "Sulfone" groups correspond to the alkyl groups defined hereinabove bonded to the molecule by an -SOO- (sulfone) bond. (CI-C 6 )sulfone includes methylsulfone, ethylsulfone, propylsulfone, 15 butylsulfone, pentylsulfone, hexylsulfone and the other isomeric forms thereof. (C 1

-C

3 )sulfone includes methylsulfone, ethylsulfone and propylsulfone. "Sulfoxyde" groups correspond to the alkyl groups defined hereinabove bonded to the molecule by an -SO- (sulfoxide) group. (C 1

-C

6 )sulfoxide includes methylsulfoxide, ethylsulfoxide, 20 propylsulfoxide, butylsulfoxide, pentylsulfoxide, hexylsulfoxide and the other isomeric forms thereof. (C 1

-C

3 )sulfoxide includes methylsulfoxide, ethylsulfoxide, propylsulfoxide and isopropylsulfoxide. "Heteroatom" denotes N, S, or O. 25 "Nucleoside" includes adenosine, thymine, uridine, cytidine and guanosine. In a particular embodiment, the hydrocarbon group is a cycloalkylenyl such as a cyclopentadiene or a phenyl, or an heterocycle such as a furan, a pyrrole, a thiophene, a thiazole, an imidazole, a 30 triazole, a pyridine, a pyrimidine, a pyrane, or a pyrazine. Preferably, the cycloalkylenyl or the heterocycle is selected from the group consisting of a cyclopentadiene, a pyrrole or an imidazole. In a preferred embodiment, the cycloalkylenyl or the heterocycle is sustituted by an alcohol. Preferably, said alcohol is a (C 1

-C

3 )alcohol. 35 In an other embodiment, the hydrocarbon group is an alkylenyl with one or several double bonds. Preferably, the alkylenyl group has one double bond. Preferably, the alkylenyl group is a (C 3 C 0 lo)alkylenyl group, more preferably a (C 4

-C

7 )alkylenyl group. Preferably, said alkylenyl group is WO 2006/103568 PCT/IB2006/001206 17 substituted by at least one functional group. More preferably, the functional group is selected from the group consisting of an hydroxy, an (C1-C 3 )alkoxy, an aldehyde, an (C 2

-C

3 )acyl, or an (C 2 C 3 )ester. In a more preferred embodiment, the hydrocarbon group is butenyl substituted by a group

-CH

2 OH. Optionally, said alkenyl group can be the isoform trans (E) or cis (Z), more preferably a 5 trans isoform (Z). In one example, the alkylenyl group is (E or Z)-4-hydroxy-2-methylbut-2-enyl. In a particular embodiment, the compound is (E or Z) 5-hydroxy-3-methylpent-3-enyl pyrophosphonate or (E or Z) 4-hydroxy-2-methylbut-2-enyl pyrophosphoramidate. In an additional embodiment, the hydrocarbon group is an alkyl group substituted by an acyl. More 10 preferably, the hydrocarbon group is an (C 4

-C

7 )alkyl group substituted by an (C 1

-C

3 )acyl. In a further particular preferred embodiment, R is selected from the group consisting of: 1) OH - (CH 2

)

n - C - R 2 I R, wherein n is an integer from 2 to 20, RI is a (C 1

-C

3 )alkyl group, and R2 is an halogenated (C 1 15 C 3 )alkyl, a (CI-C 3 )alkoxy-(C 1

-C

3 )alkyl, an halogenated (C 2

-C

3 )acyl or a (C 1

-C

3 )alkoxy-(C 2

-C

3 )acyl. Preferably, R, is a methyl or ethyl group, and R2 is an halogenated methyl (-CH 2 -X, X being an halogen), an halogenated (C 2

-C

3 )acetyl, or (C 1

-C

3 )alkoxy- acetyl. The halogenated methyl or acetyl can be mono-, di-, or tri-halogenated. Preferably, n is an integer from 2 to 10, or from 2 to 5. In a more preferred embodiment, n is 2. In a most preferred embodiment, n is 2, R, is a methyl and R2 is 20 an halogenated methyl, more preferably a monohalogenated methyl, still more preferably a bromomethyl or iodomethyl. In a particularly preferred embodiment, n is 2, R, is a methyl, R2 is a bromomethyl. In a most preferred embodiment, R is 3-(bromomethyl)-3-butanol-l-yl. 2) 0 CH 2 - (CH 2 )n R 25 wherein n is an integer from 2 to 20, and R, is a methyl or ethyl group. Preferably, n is an integer from 2 to 10, or from 2 to 5. In a more preferred embodiment, n is 2 and R1 is a methyl. 3) WO 2006/103568 PCT/IB2006/001206 18 R3 I /R5

-

C- W'= C Cl R i W"'--C R6 R4 wherein R3, R 4 , and R 6 , identical or different, are a hydrogen or (C 1

-C

3 )alkyl group or any other isosteric group, W' is CH or N, and R5 is an (C 2

-C

3 )acyl, an aldehyde, an (C 1

-C

3 )alcohol, or an (C 2 C 3 )ester. More preferably, R6 is a methyl and R3 and R 4 are a hydrogen. Preferably, R5 is -CH 2 -OH, 5 -CHO, -CO-CH 3 or -CO-OCH 3 . More preferably, R5 is -CH 2 -OH. More preferably, W' is CH. Optionally, the double-bond between W and C is in conformation trans (E) or cis (Z). More preferably, the double-bond between W and C is in conformation trans (E). The Y group can allow the design of a prodrug. Therefore, Y is enzymolabile group which can be 10 cleaved in particular regions. The group Y can also be targeting group. In a preferred embodiment, Y is O'Cat+, a group -A-R, or a radical selected from the group consisting of a nucleoside, a monosaccharide, an epoxyde and a halohydrin. Preferably, Y is an enzymolabile group. Preferably, Y is O'Cat+, a group -A-R, or a nucleoside. In a first preferred embodiment, Y is O-Cat+. In a second preferred embodiment, Y is a nucleoside. 15 In a preferred embodiment, Cat + is H

+

, Na

+

, NH4

+

, K, Li

+

, (CH 3

CH

2

)

3 NH, lysine, or any other suitable pharmaceutically acceptable cation. In a preferred embodiment, A is O, NH, CHF, CF 2 or CH 2 . Preferably, A is O, NH or CH 2 . More 20 preferably, A is O, or CH 2 . Still more preferably, A is O. In a preferred embodiment, B is O or NH. More preferably, B is O. In a preferred embodiment, m is 1 or 2. More preferably, m is 1. 25 In a preferred embodiment,, R3, R 6 and R 4 are a hydrogen. In a preferred embodiment, R5 is -CH 2 -OH, -CHO, -CO-CH 3 or -CO-OCH 3 . More preferably, R5 is

-CH

2 -OH. 30 In a preferred embodiment, R7 is CH 3 or an isosteric group thereof, such as CH 2 F, CF 2 H or CF 3 . More preferably, R7 is CH 3

.

WO 2006/103568 PCT/IB2006/001206 19 In a futher aspect, said activator is a compound selected from the group consisting of: * A compound of Formula (II): R6 R3 O O C-C-C-A- -P-B- -P-Y R5I I I I R7 R4 O-Cat+ O-Cat+ m (II) 5 wherein Cat+ represents one (or several, identical or different) organic or mineral cation(s) (including proton); m is an integer from 1 to 3; B is O, NH, or any other group capable of being hydrolyzed; A is O, NH, CHF, CF 2 or CH 2 , or any other isosteric group; 10 R7 is a (C 1

-C

3 )alkyl group or any other isosteric group such as CF 3 ; R3, R 4 , and R 6 , identical or different, are a hydrogen or a (Cl-C 3 )alkyl group or any other isosteric group such as CF3; R5 is an (C 2

-C

3 )acyl, an aldehyde, an (C 1

-C

3 )alcohol, or an (C 2

-C

3 )ester; and, Y is defined as in Formula (I). 15 Preferably, A is O or CH 2 . More preferably, A is O. More preferably, R3, R 6 and R4 are a hydrogen. Preferably, R7 is CH3 or an isosteric group thereof. More preferably, R7 is CH 3 . Preferably, R5 is CH 2 -OH, -CHO, -CO-CH 3 or -CO-OCH 3 . More preferably, R5 is -CH 2 -OH. Preferably, Y is O0 Cat+. Preferably, m is 1. Preferably, B is OIn one embodiment, the group R5 and the moiety CR 3 R4-A-[POOB]m-POOY of formula (II) are in E (or trans) configuration. In a preferred 20 embodiment, the group R5 and the moiety -CR 3

R

4 -A-[POOB]m-POOY of formula (II) are in Z (or cis) configuration. * A compound of Formula (111): R3 0 O I II Ti R5-N=C-C-A- -P-B- -P-Y I I I I t7 R4 O-Cat+ O-Cat+ m (fl) 25 wherein Cat+ represents one (or several, identical or different) organic or mineral cation(s) (including proton); m is an integer from 1 to 3; WO 2006/103568 PCT/IB2006/001206 20 B is O, NH, or any other group capable of being hydrolyzed; A is O, NH, CHF, CF 2 or CH 2 , or any other isosteric group such as CF 3 ; R7 is a (C 1

-C

3 )alkyl group or any other isosteric group such as CF 3 ; R3, and R 4 , identical or different, are a hydrogen or a (CI-C 3 )alkyl group or any other 5 isosteric group such as CF 3 ; R5 is an (C 2

-C

3 )acyl, an aldehyde, an (Cl-C 3 )alcohol, or an (C 2

-C

3 )ester; and, Y is defined as in Formula (I). Preferably, A is O or CH 2 . More preferably, A is O. More preferably, R3 and R 4 are a hydrogen. Preferably, Rs is -CH 2 -OH, -CHO, -CO-CH 3 or -CO-OCH 3 . More preferably, R5 is -CH 2 -OH. 10 Preferably, Y is O-Cat+. Preferably, m is 1. Preferably, B is O. Preferably, R7 is CH 3 or an isosteric group thereof, such as CH 2 F, CF2H or CF 3 . More preferably, R 7 is CH 3 . In one embodiment, the group R5 and the moiety -CR 3

R

4 -A-[POOB]m-POOY of formula (111) are in E (or trans) configuration. In a preferred embodiment, the group R 5 and the moiety -CR 3

R

4 -A-[POOB]m-POOY of formula (III) are in Z (or cis) configuration. 15 * A compound of Formula (IV): R3 O O HOCH2 W'C-C-A- -P-B- -1P Y' I I I I R7 R4 O-Cat+ O-Cat+ m (IV) wherein Cat+ represents one (or several, identical or different) organic or mineral cation(s) (including proton); 20 m is an integer from 1 to 3, B is O, NH, or any other group capable of being hydrolysed, A is O, NH, CHF, CF 2 or CH 2 , and, W is C-R 6 or N; R7 is a (C 1

-C

3 )alkyl group or any other isosteric group such as CF 3 , 25 R3, R 4 , and R 6 , identical or different, are a hydrogen or a (C 1

-C

3 )alkyl group or any other isosteric group, and Y is defined as in Formula (I). Preferably, A is O or CH 2 . More preferably, A is O. More preferably, R3, R 6 and R4 are a hydrogen. Preferably, R7 is CH3 or an isosteric group thereof. More preferably, R7 is CH3. Preferably, Y is O 30 Cat+. Preferably, m is 1. Preferably, B is O. In one embodiment, the group -CH 2 -OH and the moiety -CR 3 R4-A-[POOB]m-POOY of formula (IV) are in E (or trans) configuration. In a preferred WO 2006/103568 PCT/IB2006/001206 21 embodiment, the group -CH 2 -OH and the moiety -CR 3

R

4 -A-[POOB]m-POOY of formula (IV) are in Z (or cis) configuration. * A compound of Formula (V): R3 O O I II iIr R5-WC-C-A- -P-B- -P-Y I I 1 1 CH R4 O-Cat+ O-Cat+ 5 -V)m wherein Cat+ represents one (or several, identical or different) organic or mineral cation(s) (including proton); m is an integer from 1 to 3, B is O, NH, or any other group capable of being hydrolysed, 10 A is O, NH, CHF, CF 2 or CH 2 , W is C-R 6 or N;

R

3 , R 4 , and R 6 , identical or different, are a hydrogen or (C 1

-C

3 )alkyl group or an isosteric group, R5 is an (C 2

-C

3 )acyl, an aldehyde, an (C 1

-C

3 )alcohol, or an (C 2

-C

3 )ester, and 15 Y is defined as in Formula (I). Preferably, A is O or CH 2 . More preferably, A is O. More preferably, R3, R 6 and R4 are a hydrogen. Preferably, R5 is -CH 2 -OH, -CHO, -CO-CH 3 or -CO-OCH 3 . More preferably, R5 is -CH 2 -OH. Preferably, Y is O-Cat+. Preferably, m is 1. Preferably, B is O. In one embodiment, the compound of formula (V) is in E (or trans) configuration. In a preferred embodiment, the group compound of 20 formula (V) is in Z (or cis) configuration. * A compound of Formula (VI): R3 O O I I II II HOCH-WC-C-A P-B- P-Y

CH

3 R4 O-Cat+ O-Cat+ m (VI) wherein Cat+ represents one (or several, identical or different) organic or mineral cation(s) 25 (including proton); m is an integer from 1 to 3, B is O, NH, or any other group capable of being hydrolysed, WO 2006/103568 PCT/IB2006/001206 22 A is O, NH, CHF, CF 2 or CH 2 ; and, W is C-R 6 or N; R3, R 4 , and R 6 , identical or different, are a hydrogen or (C 1

-C

3 )alkyl group or an isosteric group, 5 Y is defined as in Formula (I). Preferably, A is O or CH 2 . More preferably, A is O. More preferably, R 3 , R 6 and R4 are a hydrogen. Preferably, Y is O'Cat+. Preferably, m is 1. Preferably, B is O. In one embodiment, the compound of formula (VI) is in E (or trans) configuration. In a preferred embodiment, the compound of formula (VI) is in Z (or cis) configuration. 10 * A compound of Fomula (VII): R3 R8 0 0 R5-W' C-C-C-- P-B- P-Y I I I I I R7 R4 R9 O-Cat+ O-Cat+ m (VII) wherein Cat+ represents one (or several, identical or different) organic or mineral cation(s) (including proton); 15 m is an integer from 1 to 3, B is O, NH, or any other group capable of being hydrolysed, W is C-R6 or N;

R

7 is a (CI-C 3 )alkyl group or an isosteric group such as CF 3 , R3, R 4 , and R 6 , identical or different, are a hydrogen or a (C 1

-C

3 )alkyl group or an isosteric 20 group such as CF 3 ,

R

8 is H or F, R9 is H or F, Y is defined as in Formula (I), and R5 is an (C 2

-C

3 )acyl, an aldehyde, an (CI-C 3 )alcohol, or an (C 2

-C

3 )ester. 25 Preferably, R3, R 6 and R 4 are a hydrogen. Preferably, Rs is -CH 2 -OH, -CHO, -CO-CH 3 or -CO

OCH

3 , more preferably -CH 2 -OH. Preferably, R7 is CH 3 or an isosteric group thereof, more preferably CH 3 . Preferably, Y is O'Cat+. Preferably, m is 1. Preferably, B is O. Preferably, R8 and R9 are a hydrogen. In one embodiment, the group R5 and the moiety -CR 3

R

4 -A-[POOB]m-POOY of formula (VII) are in E (or trans) configuration. In a preferred embodiment, the group R5 and the 30 moiety -CR 3 R4-A-[POOB]m-POOY of formula (VII) are in Z (or cis) configuration.

WO 2006/103568 PCT/IB2006/001206 23 * A compound of Formula (VIII): R3 O O 1 11 11 R5-W=C-C-N- -P-B- -P-Y I I " H I R7 R4 O-Cat+ O-Cat+ m ~ (VII) wherein Cat+ represents one (or several, identical or different) organic or mineral cation(s) (including proton); 5 m is an integer from 1 to 3, B is O, NH, or any other group capable of being hydrolysed, W is C-R 6 or N;

R

7 is a (CI-C 3 )alkyl group or an isosteric group such as CF 3 ,

R

3 , R 4 , and R 6 , identical or different, are a hydrogen or a (Cl-C 3 )alkyl group or an isosteric 10 group such as CF3, Y is defined as in Formula (I), and

R

5 is an (C 2

-C

3 )acyl, an aldehyde, an (C 1

-C

3 )alcohol, or an (C 2

-C

3 )ester. Preferably, R 3 , R 6 and R 4 are a hydrogen. Preferably, R5 is -CH 2 -OH, -CHO, -CO-CH 3 or -CO

OCH

3 , more preferably -CH2-OH. Preferably, R7 is CH 3 or an isosteric group thereof, more 15 preferably CH 3 . Preferably, Y is O'Cat+. Preferably, m is 1. Preferably, B is O. In one embodiment, the group R5 and the moiety -CR 3

R

4 -A-[POOB]m-POOY of formula (VIII) are in E (or trans) configuration. In a preferred embodiment, the group R5 and the moiety -CR 3 R4-A-[POOB]m-POOY of formula (VIII) are in Z (or cis) configuration. 20 * A compound of Formula (IX): R3 O O I I II II HOCHWC-C -- P-B--P-Y

CH

3 R4 O-Cat+ O-Cat+ m (IX) wherein Cat+ represents one (or several, identical or different) organic or mineral cation(s) (including proton); m is an integer from 1 to 3, 25 B is O, NH, or any other group capable of being hydrolysed, W is C-R 6 or N; WO 2006/103568 PCT/IB2006/001206 24

R

3 , R 4 , and R 6 , identical or different, are a hydrogen, an (Ci-C 3 )alkyl group or an isosteric group such as CF 3 , Y is defined as in Formula (I). Preferably, R3, R 6 and R4 are a hydrogen. Preferably, Y is OCat+. Preferably, m is 1. Preferably, B 5 is O. In one embodiment, the compound of formula (IX) is in E (or trans) configuration. In a preferred embodiment, the compound of formula (IX) is in Z (or cis) configuration. * A compound of Formula (X): R3 R8 O O _ _I I II I

HOCH

2 W=C-C-C- -P-B- -P-Y I I I I I CH3 R4 R9 O-Cat+ O-Cat+ m (X) 10 wherein Cat+ represents one (or several, identical or different) organic or mineral cation(s) (including proton); m is an integer from 1 to 3, B is O, NH, or any other group capable of being hydrolysed, W is C-R6 or N; 15 R3, R4, and R 6 , identical or different, are a hydrogen, an (C 1

-C

3 )alkyl group or an isosteric group such as CF 3 , Rs is H or F, R9 is H or F, and Y is defined as in Formula (I). 20 Preferably, R 3 , R 6 and R 4 are a hydrogen. Preferably, Y is O-Cat+. Preferably, m is 1. Preferably, B is O. Preferably, Rs and R9 are a hydrogen. In one embodiment, the compound of formula (X) is in E (or trans) configuration. In a preferred embodiment, the compound of formula (X) is in Z (or cis) configuration. 25 * A compound of formula (XI): R3 O O I ft ft HOCHj-W=-C-N- -P-B- -P-Y I . I H I I

CH

3 R4 O-Cat+ O-Cat+ m

(XI)

WO 2006/103568 PCT/IB2006/001206 25 wherein Cat+ represents one (or several, identical or different) organic or mineral cation(s) (including proton); m is an integer from 1 to 3, B is O, NH, or any other group capable of being hydrolysed, 5 W is C-R 6 or N; R3, R 4 , and R 6 , identical or different, are a hydrogen, an (C 1

-C

3 )alkyl group or an isosteric group such as CF 3 , and Y is defined as in Formula (I). Preferably, 1R3, R 6 and R 4 are a hydrogen. Preferably, Y is OCat+. Preferably, m is 1. Preferably, B 10 is O. In one embodiment, the compound of formula (XI) is in E (or trans) configuration. In a preferred embodiment, the compound of formula (XI) is in Z (or cis) configuration. In further embodiments, the y8 T cell activator is a compound of formula (XII) or (XII'): OH O 0 III O-P-O-P-O-Cat* I I O-Cat+ O-Cat + (XII) 15 (Z)-4-hydroxy-2-methylbut-2-enyl pyrophosphate (also referred to as HAngelylPP) O O HO II II H - O-P-0-P O-Cat' I I O-Cat+ O-Cat + (XIP) (E)-4-hydroxy-2-methylbut-2-enyl pyrophosphate (also referred to as HTiglylPP) In further embodiments, the y8 T cell activator is a compound of formula (XIII) or (XIII'): OH P-O-P-O-Cat* YI +I 20 O-Cat OCat+ (XIII) (Z)-5-hydroxy-3-methylpent-3-enyl pyrophosphonate (also referred to as C-HAngelylPP) O O HO ypsha 1 11 HO P-0---OCat* I I OhCatn p OCat e X(I) (E)-5-hydroxy-3-methylpent-3-enyl pyrophosphonate (also referred to as C-HTiglylPP) WO 2006/103568 PCT/IB2006/001206 26 In further embodiments, the y8 T cell activator is a compound of formula (XIV) or (XIV'): OH O 0 N-P-O-P--Cat H I + I O'Cat O'Cat* (XIV) (Z)-4-hydroxy-2-methylbut-2-enyl pyrophosphoramidate (also referred to as N-HAngelylPP) O O HO II II S - N-P-0-P-O-Cat + H I + I O-Cat O-Cat+ (XIV') 5 (E)-4-hydroxy-2-methylbut-2-enyl pyrophosphoramidate (also referred to as N-HTiglylPP) In further embodiments, the y8 T cell activator is a compound of formula (XV): O z NH OH NO 0 0 0 N_ II II II A-P-O-P-O-P-O Io- I° I O-Cat O-Cat+ O'Cat+ H H OH X (XV) wherein Cat+ and A are defined as in Formula (I); X is H and Z is CH 3 (deoxyribonucleoside is 10 thymydine) or X is OH and Z is H (ribonucleoside is uridine) In one embodiment, the compound of formula (XV) is in E (or trans) configuration. In a preferred embodiment, the compound of formula (XV) is in Z (or cis) configuration. Synthesis 15 As a general principle for exemplary methods, an alkyl moiety is prepared in a first step and coupled to a phosphorous containing moiety. For the sake of simplicity, the following schemes are shown for compounds where Y is O-Cat+. If a different Y group is desired, this can be prepared in a further step as described herein. 20 Depending on the type and reactivity of the functional groups provided by the alkyl moiety (represented by R in the discussion below), the person of skill in the art is able to adapt synthesis WO 2006/103568 PCT/IB2006/001206 27 examples presented herein if necessary including the phases of protection/deprotection of the sensitive functional groups or those that can interact with the coupling reaction. The coupling step is generally the critical step for synthesis and purification. A number of 5 examples for coupling are provided as follows, depending on the identity of at position A. Phosphate monoesters of Formula I or II, where A is O and where Y is O-Cat+, can be prepared using a coupling step according to conditions similar to those described in any of the publications: Davisson et al. (1984) and Davisson et al. (1987) and US Patent No. 6,660,723 to Belmant et al., 10 the disclosures of each of which are incorporated herein by reference. Phosphoramidate monoesters of Formula I or II, where A is NH and where Y is O-Cat+, can be prepared using a coupling step according to conditions similar to those described in any of the publications: Cox et al. (2002) and Sato et al. (1990) and copending PCT patent application nos. 15 PCT/IB2004/004311 and 60/579,237 to Belmant et al., the disclosures of each of which are incorporated herein by reference. Phosphonate monoesters of Formula I or II, where A is CH2 and where Y is O-Cat+, can be prepared using a coupling step according to conditions similar to those described in publications: 20 Valentijn (1991); Cox et al (2002), US provisional patent applications 60/629,069, 60/564,959 to Tiollier, and PCT patent publication no. WO 03/050128, the disclosures of each of which are incorporated herein by reference. Difluoro- and monofluorophosphonate monoesters of Formula I or II, where A is CF or CF2 and 25 where Y is O-Cat+, can be prepared using a coupling step according to conditions similar to those described in publications: Cox et al. (2002), Waschbusch et al. (1997) and Burton et al. (1989), the disclosures of each of which are incorporated herein by reference. Angelyl phosphoesters can be purified by preparative reversed phase HPLC on C18 according to 30 the method reported by Zhang & Poulter (1993), by preparative chromatography on silica gel using ammoniac isopropanol eluents according to the methods of International Patent publication no. WO 03/050128 filed 5 December 2002 for compounds having a good chemical stability in basic medium (phosphonate and angelyl phosphoesteres), or by chromatography on cellulse Davisson et al. (1984). The disclosures of the above references are incorporated herein by reference. 35 Compounds comprising a nucleoside as Y group can be prepared, for example, by the following reactions, WO 2006/103568 PCT/IB2006/001206 28 Nucl-O-V, acetonitrile R-A-PP 0 R-A-PP-O-Nucl Reaction A or Nucl-O-V, acetonitrile 5 R-A-PPP > R-A-PPP-O-Nucl Reaction B where -O-V is a good leaving group beginning with V chosen, for example, from among tosyle, mesyle, triflyle, brosyle or bromium, PP represents the pyrophosphate group, PPP represents the 10 triphosphate group, R-A- has the above mentionned meaning and Nucl is a nucleoside. Preferably, Nucl-O-V is selected from the group consisting of: 5'-O-Tosyladenosine, 5'-O-Tosyluridine, 5'-0 Tosylcytidine, 5'-O-Tosylthymidine or 5'-O-Tosyl-2'-deoxyadenosine. Depending on the type and reactivity of the functional groups provided by Y, the professional is 15 able to adapt the following examples, if necessary including the phases of protection/non protection of the sensitive functional groups or those that can interact with the coupling reaction. For example, for the compound with R as shown below, the reaction procedure can be the following: 20

CH

2 0O(PG) CH 2 0(PG) H5'-O-Tosyluridine, acetonitrile H O-PPP > H O-PPP-O- Uridine

CH

2 OH alcohol deprotection H O-PPP-O-Uridine 0. H O-PPP-O-Urdino where PG represents a protective group of the alcohol function, and where -0O-V is a good leaving group beginning with V chosen, for example, from among tosyle, mesyle, triflyle, brosyle or 25 bromium, PP represents the pyrophosphate group and Nucl is a nucleoside. Preferably, Nucl-O-V is selected from the group consisting of: 5'-O-Tosyladenosine, 5'-O-Tosyluridine, 5'-O Tosylcytidine, 5'-O-Tosylthymidine or 5'-O-Tosyl-2'-deoxyadenosine as described in Davisson et al, (1987), the disclosure of which is incorporated herein by reference.

WO 2006/103568 PCT/IB2006/001206 29 Neutral pH is a nucleophile substitution reaction that can be carried out in conditions similar to those described by Davisson et al, (1987); and Davisson et al. (1986), the disclosures of which are incorporated herein by reference. 5 This reaction can also be used to prepare compound comprising a monosaccharide as group Y. In this case, Nucl-O-V is replaced by MonoSac-O-V, wherein Monosac is monosaccharide. For example, it is possible to use the MonoSac-O-Y group corresponding to compound Methyl-6-O tosyl-alpha-D-galactopyranoside as described in publication Nilsson and Mosbach (1980), which disclosure is incorporated herein by reference, or the commercially available mannose triflate 10 compound. This reaction can further be used to prepare compound comprising a oligosaccharide as group Y. In this case, Nucl-O-V is replaced by oligoSac-O-V, wherein oligoSac is an oligosaccharide. For example, it is possible to use the oligoSac-O-Y group corresponding to compound 6 A-O-p 15 Toluenesulfonyl-B-cyclodextrin as described in publication (Organic syntheses, Vol. 77, p 225-228, the disclosure of which is incorporated herein by reference). This reaction can be used to prepare compound comprising a polysaccharide as group Y. In this case, Nucl-O-V is replaced by polySac-O-V, wherein polySac is a polysaccharide. For example, it 20 is possible to use the polySac-O-Y group corresponding to tosylated polysaccharide as described in publication Nilsson et al., (1981); and Nilsson and Mosbach, (1980), the disclosures of which are incorporated herein by reference. This coupling technique based on the activation of the hydroxyl groups of a polysaccharide support by tosylation allows for covalent coupling in an aqueous or an organic medium. 25 This reaction can also be used for preparing compound comprising an aldehyde derivative as group Y by choosing, instead of Nucl, a derivative including a protected aldehyde function in the form of an acetal or any other group protecting this function. 30 Alternatively, compounds comprising a nucleoside as Y group can be prepared by the following reaction: 1) Nucl-O-PPP, carbodiimide DMF/Methanol R-AH a R-A-PPP-O-Nucl 2) Triethylamine, DMF Reaction C WO 2006/103568 PCT/IB2006/001206 30 where PPP represents the triphosphate group, A is O or NH with R-AH representing a primary alcohol (R-OH) or a primary amine (R-NH 2 ), DMF is dimethylformamide, and Nucl is a nucleoside. This reaction can be carried out in conditions similar to those described by Knorre et 5 al.(1976), or by Bloom et al., United States Patent No. 5,639,653 (1997), the disclosures of which are incorporated herein by reference, from an alcohol and a nucleotide with formula Nucl-O-PPP. For example, for the compound with R as shown below, the reaction procedure can be the following: 10

CH

2 0(PG)

CH

2 0(PG) 1) UTP (Bu 4 N' salt), carbodiimide DMF / Methanol H NH 2 I H N-PPP-O- Uridin 2) Triethylamine, DMF H

CH

2 OH alcohol deprotection H N-PPP-- Uridine H where PG represents a protective group of the alcohol function, UTP is Uridine Triphosphate, PPP represents the triphosphate group, DMF is dimethylformamide, and Nucl is a nucleoside. 15 This reaction can also be applied to the preparation of oligonucleotides 5'-triphosphate 7-esters as indicated by the authors of publication Knorre et al. (1976). Compounds comprising a nucleic acid as Y group, more particularly a ribonucleic acid, can be 20 prepared in conditions similar to those described in publication F. Huang et al (1997). The authors describe a universal method from catalytic RNA that is applicable to any molecule comprising a free terminal phosphate group. Compounds structurally related to the phosphohalohydrine group such as isopentenyl pyrophosphate or thiamine pyrophosphate are used or mentioned by these authors (see p. 8968 of F. Huang et al (1997)). It should also be noted that the experimental 25 conditions for the coupling procedure (in particular pH conditions) described in the section <Reaction of Isolate 6 pppRNA with phosphate containing Nucleophiles>> on page 8965 are compatible with the presence of a halohydrine function. Compounds comprising an amino acid, a peptide or a protein derivative as Y group can be obtained 30 using the well known reactivity of their primary amine or thiol function on an epoxyde function WO 2006/103568 PCT/IB2006/001206 31

(SN

2 reaction). This type of coupling classically involves an intermediate group still called "linker" bearing an epoxyde function. An example of a reaction procedure using this type of coupling is provided by the following scheme, tosylate glycidyl R- A-PP or epichlorohydrine R-A-PPO-CH 2 R- -P >R- A-PPO- CH 2 acetonitrile R'-SH R- A-OPPO-CH 2

-CH

2 OH-S-R' 5 Y Reaction D where PP represents the pyrophosphate group, R-A has the above mentioned meaning and R'-SH is an amino acid, a peptide or a protein derivative. The first phase can be carried out in conditions 10 similar to those described by Davisson et al. (1987) and Davisson et al, (1986), the disclosures of which are incorporated herein by reference, from the tetrabutylammonium salt of the initial compound and commercially available compounds such as glycidyl tosylate or epichlorohydrine. This reaction can also be carried out with thriphosphate compounds. Alternatively, a primary amine

R'-NH

2 can be used instead of R'-SH. Without the reaction with R'-SH, the first reaction can be 15 used to prepare compound comprising an epoxyde derivative. Alternatively, compounds comprising an amino acid, a peptide or a protein derivative as Y group can be prepared by the following reaction: 1) R-NH2, carbodiimide DMF/Methanol R- A- PPP DMF/Methanol R- A- PPO -P-NH-R' 20 2) Triethylamine, DMF Reaction E where PPP represents the triphosphate group, PP represents the pyrophosphate group, P represents the phosphate group, R-A has the above mentionned meaning and R'-NH is an amino acid, a 25 peptide or a protein derivative. The reaction can be carried out in conditions similar to those described by Knorre et al. (1976), the disclosure of which is incorporated herein by reference, from compound (R-A-PPP) and an amino acid, peptide or a protein with formula R-NH 2 . This reaction WO 2006/103568 PCT/IB2006/001206 32 involves the protection of the sensitive functions of compound R-NH 2 or can react with the carbodiimide (in particular, the carboxyl function). Tri or tetra-n-butylammonium salts of phosphoric, pyrophosphoric, triphosphoric, tetra-phosphoric 5 or polyphosphoric acid can be prepared from commercially available corresponding acids. Derivatives with a related structure such as derivatives of methanetrisphosphonic acid described in publication Liu et al (1999), the disclosure of which is incorporated herein by reference, can also be prepared according to the reaction procedure. 10 The above mentionned reactions can be extrapolated to a very large spectrum of molecules or biomolecules by using the reactivity of the hydroxyl, amine, phosphate or thiol functions. Thereby, inositol derivatives can be prepared according to reactions A or B by activation of the hydroxyl function. Derivatives of folic acid (vitamin B9) or tetrahydrofolic acid can be prepared according to reactions D or E by calling on the reactivity of the primary amine function. 15 Of course, other types of coupling can be considered and the professional can have access to a large choice of reactions. Thereby, coupling by phosphorylation of carboxylic acid or phenol groups can be used for the 20 formation of fatty acid, lipid or certain flavonoid derivatives. Assessing activity of compounds The angelyl and tiglyl phosphoesters can be produced ex vivo or in vitro. They may be a purified or 25 otherwise artificially produced (e.g., by chemical synthesis, or by microbiological process). The angelyl phosphoesters according to the present invention are preferably capable of activating Vy9V82 T lymphocytes. In a preferred embodiment, the compound is capable of selectively activating Vy9V82 T lymphocytes, indicating that the compound has a selective action towards specific cell populations, and essentially does not directly activate other T cell sub-types, such as 30 V81 T cells. Such selectivity, as disclosed in the present application, suggests that preferred compounds can cause a selective or targeted activation of the proliferation or biological activity of Vy9V82 T lymphocytes. The angelyl phosphoesters preferably increases the biological activity or causes the proliferation of 35 y8 T cells, preferably increasing the activation of '8 T cells, particularly increasing cytokine secretion from y8 T cells or increasing the cytolytic activity of y5 T cells, with or without also WO 2006/103568 PCT/IB2006/001206 33 stimulating the proliferation or expansion of y8 T cells. Accordingly, the angelyl or tiglyl phosphoesters is administered in an amount and under conditions sufficient to increase the activity y8 T cells in a subject, preferably in an amount and under conditions sufficient to increase cytokine secretion by y8 T cells and/or to increase the cytolytic activity of y8 T cells. Cytokine secretion and 5 cytolytic activity as well as y8 T cell proliferation can be assessed using any appropriate in vitro assay. Most preferably the y8 T cells referred to in the present specification are Vy9V82 T cells, and preferably the angelyl and tiglyl phosphoesters regulate the activity of Vy9V82 T cells. 10 In one example, y78 T cell activation can be assessed by administering a compound to an individual (human or non-human primate) and assessing activation or proliferation of Vy9V82 T cell. In an exemplary protocol expansion of the Vy9V82 T cell population is assessed: an angelyl phosphoester is administered to a non-human primate such as a cynomolgus monkey by 15 intravenous infusion (one administration by slow infusion, 50 ml over 30 minutes) in combination with 1L-2 (0.9 million units twice daily by subcutaneous injection for 5 days); peripheral y 8 lymphocytes are analysed by flow cytometry on total monkey blood, after double staining with anti-CD3-PE antibody and anti-Vgamma9-FITC antibodies and/or anti Vd2 antibodies, and cells are counted by flow cytometry. Peak expansion of the Vy9V82 T cell population is observed 20 between days 3 and 8, generally at about days 4-6 after administration of an angelyl phosphoester. Any other suitable tests can be used to assess cell proliferation. Assessment of proliferation or peripheral y8 lymphocytes can generally be analyzed by flow cytometry on total blood (for example total blood obtained from a monkey), after double staining with anti-CD3-PE antibody 25 and anti-Vgamma9-FITC antibodies and/or anti Vd2 antibodies (CD3-PE: SP34 clone, BD Biosciences Pharmingen, Le Pont de Claix, France). Anti Vgamma 9, clone 7B6 is a monoclonal raised to human Vgamma 9 but that cross-reacts with cynomolgus monkey cells. It is purified by affinity chromatography on protein A and coupled to FITC. 50[l monkey blood is incubated 15 min at RT with 5[l anti-CD3-PE and 6[l anti-delta2-FITC or 10[l anti-gamma9-FITC antibodies. 30 Antibodies are washed with 3ml 1X PBS, centrifuged for 4 min at 1300rpm at RT and supernatant is discarded. Red cells are lysed with the OptiLyse C reagent (Inimmunotech-Beckman-Coulter, Marseilles, France) according to the manufacturer's instructions. At the final step, stained white blood cells are recovered by centrifugation and resuspended in 300gl PBS + 0.2% PFA. Immediately before analysis, 50pl calibrated Flow CountTM Fluorospheres (Immunotech-Beckman 35 Coulter, Marseilles, France) are added to the cells for absolute number counting of the populations of interest.

WO 2006/103568 PCT/IB2006/001206 34 Preferably an angelyl phosphoester is capable of regulating the activity of a 'y8 T cell in a population of y8T cell clones in culture. The angelyl phosphoester is more preferably capable of regulating the activity of a yS. T cell population of y8T cell clones in culture at millimolar 5 concentration, preferably when the angelyl phosphoester is present in culture at a concentration of less than 100 mM. In one example, cytokine production or release is assessed. Vg9Vd2 cells are known producers of TNFo and IFNy in vitro upon administration of the angelyl phosphoester. Shortly after angelyl phosphoester treatment, samples of sera are collected from an individual and are assayed by ELISA specific for TNFo or IFNy. 10 Regulating the activity of a y8. T cell can be assessed by any suitable means, preferably by assessing cytokine secretion, most preferably TNF-oc secretion as described herein. Methods for obtaining a population of pure y8 T cell clones is described in Davodeau et al, (1993) and Moreau et al, (1986), the disclosures of which are incorporated herein by reference. 15 In any exemplary assay, cytokine secretion can be determined according to the methods described in Espinosa et al. (2001a), describing measurement of TNF-a release in a bioassay using TNF-ax sensitive cells. Briefly, 10 4 ¥6T cells/well were incubated with stimulus plus 25 units ofIL2/well in 100 tl of culture medium during 24 h at 37 oC. Then, 50 gl of supernatant were added to 50 .l of 20 WEHI cells plated at 3 x 104 cells/well in culture medium plus actinomycin D (2 tg/ml) and LiC1 (40 mM) and incubated for 20 h at 37 oC. Viability of the TNF-c-sensitive cells and measured with a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. 50 pl of 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (Sigma; 2.5 mg/ml in phosphate-buffered saline) per well were added, and after 4 h of incubation at 37 oC, 50 pl of solubilization buffer (20% 25 SDS, 66% dimethyl formamide, pH 4.7) were added, and absorbance (570 nm) was measured. Levels of TNF-c release were then calculated from a standard curve obtained using purified human rTNF-m (PeproTech, Inc., Rocky Hill, NJ). Interferon-Y released by activated T cells was measured by a sandwich enzyme-linked immunosorbent assay. 5 x 104 Y5T cells/well were incubated with stimulus plus 25 units of L2/well in 100 pl of culture medium during 24 h at 37 'C. Then, 50 [l of 30 supernatant were harvested for enzyme-linked immunosorbent assay using mouse monoclonal antibodies (BIOSOURCE, Camarillo, CA). A preferred assay for cytolytic activity is a 51 Cr release assay. In exemplary assays, the cytolytic activity of y8 T cells is measured against autologous normal and tumor target cell lines, or control 35 sensitive target cell lines such as Daudi and control resistant target cell line such as Raji in 4h 5 1 Cr release assay. In a specific example, target cells were used in amounts of 2x103 cells/well and WO 2006/103568 PCT/IB2006/001206 35 labeled with 100 tCi 51 Cr for 60 minutes. Effector/Target (E/T) ratio ranged from 30:1 to 3.75: 1. Specific lysis (expressed as percentage) is calculated using the standard formula [(experimental spontaneous release / total-spontaneous release) x100]. 5 Use ofphosphoester according to the present invention The invention concerns a pharmaceutical composition comprising an angelyl or tiglyl phosphoester according to the present invention. More particularly, said pharmaceutical composition comprises a therapeutically effective amount of an angelyl or tiglyl phosphoester, optionally together with a 10 pharmaceutically acceptable carrier. The present invention concerns an angelyl or tiglyl phosphoester according to the present invention as a medicament. Also encompassed by the invention is the use of an angelyl or tiglyl phosphoester according to the present invention for the manufacture of a pharmaceutical preparation, preferably for the treatment of a cancer, an infectious disease, an autoimmune disease or an allergic disease. 15 In one aspect, the invention discloses a method for regulating the activity of y8 T cells in a human subject, said method comprising the step of administering, in at least one treatment, a therapeutically effective amount of an angelyl or tiglyl phosphoester according to the present invention, optionally together with a pharmaceutically acceptable carrier. More particularly, said 20 method activates of stimulates an activity of y8 T cells in a human subject. In a particular embodiment, the amount of said angelyl or tiglyl phosphoester is sufficient to expand the y8 T cell population in a subject to reach at least 10%, 15%, 20%, 30%, 40%, 50% or 60%, or between 30-90% of total circulating lymphocytes. In another embodiment, the amount of 25 said angelyl or tiglyl phosphoester is sufficient to induce an at least 10-fold increase in the y8 T cell population in a subject. Preferably, said y8 T cell population is assessed between day 4 and day 8 following administration of said angelyl phosphoester, more preferably at day 5, 6 or 7 following administration of said angelyl phosphoester. Preferably, said y8 T cell population is assessed by flow cytometry. Preferably, said y8 T cells are Vy9/V82 T cells. 30 In a preferred embodiment, the invention concerns a method for treating a cancer, an infectious disease, an autoimmune disease or an allergic disease in a subject, said method comprising the step of administering, in at least one treatment, a therapeutically effective amount of an angelyl or tiglyl phosphoester according to the present invention, optionally together with a pharmaceutically 35 acceptable carrier.

WO 2006/103568 PCT/IB2006/001206 36 In the above methods and uses, the subject is preferably a human subject, such as a subject having a cancer, an infectious disease, an autoimmune disease or an allergic disease. The invention is indeed suitable to treat all conditions caused by or associated with the presence of pathological cells which are sensitive to y8 T cell lysis. 5 The invention is particularly suited to stimulate the anti-tumor immunity of a subject having a solid or hematopoietic tumor. Preferably, said tumor is selected from the group consisting of lung, colorectal, prostate, breast or epidermoid head or neck tumors. In a preferred aspect of the invention, said tumor is a renal cancer, preferably a metastatic renal cancer. Alternatively, said 10 tumor is selected from the group consisting of a melanoma, ovarian cancer, pancreas cancer, neuroblastoma, head or neck cancer, bladder cancer, renal cancer, brain cancer and gastric cancer. In preferred embodiments, the compounds can be used for the treatment of cancer as described in International Patent Application number WO2004050096, the disclosure of which is incorporated herein by reference. 15 The invention is also suitable to stimulate an anti-viral immune response in a subject. For example the compound of the invention can be used for the treatment of an individual having an infection by a virus selected from HIV, CMV, EBV, Influenza virus, HPV, HCV and HBV. 20 The compounds of the invention are also suitable in methods of stimulating an immune response in a subject having an infection by a pathogen causing tuberculosis, malaria, tularemia, colibacillosis, etc. The compounds of the invention are also suitable in methods of treating (e.g., for stimulating an 25 immune response in) a subject having an autoimmune disease, such as diabetes, multiple sclerosis, rheumatoid arthritis, etc. or a subject having an allergic disease, including asthma, airway hyper responsiveness, etc. In preferred embodiments the compounds are used in therapeutic indications and according to the teachings of International Patent publication number WO2000US0026684 filed on 28 Sep. 2000 by Gelfand, Born, Lahn, and Kanehiro; International Patent publication no. 30 WO 00/00182, filed 24 June 1999 by Jomaa; and International patent publication no WO2005/102385 by Tiollier, the disclosures of each of the references being incorporated herein by reference. Preferably, dosage (single administration) of an angelyl phosphoester compound according to the 35 present invention for treatment is between about 1 jtg/kg and about 1.2 g/kg.

WO 2006/103568 PCT/IB2006/001206 37 It will be appreciated that the above dosages related to a group of compounds, and that each particular compound may vary in optimal doses, as further described herein for exemplary compounds. Nevertheless, compounds are preferably administered in a dose sufficient to significantly increase the biological activity of y8 T cells or to significantly increase the y5 T cell 5 population in a subject. Said dose is preferably administered to the human by intravenous (i.v.) administration during 2 to 180 min, preferably 2 to 120 min, more preferably during about 5 to about 60 min, or most preferably during about 30 min or during about 60 min. In preferred exemplary compounds, a compound of Formula I to XVIII is administered in a dosage 10 (single administration) between about 1 gg/kg and about 1.2 g/kg, preferably between about 10 tg/kg and about 1.2 g/kg, more preferably between about 20 jig/kg and about 100 mg/kg. Most preferably, dosage (single administration) for three-weekly or four-weekly treatment (treatment every three weeks or every third week) is between about 1 jg/kg and about 1.2 g/kg, preferably between about 10 jg/kg and about about 20 mg/kg, more preferably between about 10 pg/kg and 15 about 100 mg/kg. This dose is preferably administered to the human by intravenous (i.v.) administration during 2 to 180 min, preferably 2 to 120 min, more preferably during about 5 to about 60 min, or most preferably during about 30 min or during about 60 min. The active ingredients may be administered through different routes, typically by injection or oral 20 administration. Injection may be carried out into various tissues, such as by intravenous, intra peritoneal, intra-arterial, intra-muscular, intra-dermic, subcutaneous, etc. Preferred administration routes for the activators are intravenous and intra-muscular. Preferred administration routes for the cytokine are subcutaneous, intravenous and intra-muscular. 25 The invention provides a method of regulating the activity of y8 T cells in a mammalian subject, the method comprising administering to a subject in need thereof an effective amount of an angelyl or tiglyl phosphoester according to a treatment cycle in which y8 T cell activity, preferably the 78 T cell rate (number of y8 T cells), is allowed to return to substantially basal rate prior to a second administration of the compound. As further described herein, in preferred embodiments, at least 30 about one week, but more preferably at least about two weeks, are required for a patient's 7 8 T cell rate to return to substantially basal rate. Cycles shorter than about 7 days may not permit suitable stimulation of 78 T cell activity. The course of a preferred cycle is an at least 1-weekly cycle, but more preferably at least a 2-weekly 35 cycle (at least about 14 days), or more preferably at least 3-weekly or 4-weekly, though cycles WO 2006/103568 PCT/IB2006/001206 38 anywhere between 2-weekly and 4-weekly are preferred. Also effective and contemplated are cycles of up to 8-weekly, for example 5-weekly, 6-weekly, 7-weekly or 8-weekly. In one preferred embodiment, administration of the angelyl or tiglyl phosphoester occurs on the 5 first day of a 2-weekly to 4-weekly cycle (that is, an about 14 to 28 day weeks repeating cycle). In a preferred embodiment, the angelyl phosphoester is administered only the first day of the 2 weekly to 4-weekly, or preferably 3 weekly, cycle. As mentioned, a subject will preferably be treated for at least two cycles, or more preferably for at 10 least three cycles. In other aspect, treatment may continue for a greater number of cycles, for example at least 4, 5, 6 or more cycles can be envisioned. Optionally, an angelyl or tiglyl phosphoester according to the present invention can also be used in combination with a cytokine, particularly for the treatment of cancer. Preferably, said cytokine is 15 the interleukin 2 (IL-2) (ProleukinTM, Chiron, Emeryville CA, USA) or any biologically active fragment, variant or analogue thereof, i.e., any fragment, variant or analogue capable of binding to an 1-2 receptor and of inducing activation of 7y5T cells in the method of this invention. In other embodiments, the cytokine is an interleukin 7 or an interleukin 15. Preferably, said angelyl or tiglyl phosphoester and said interleukin polypeptide are administered separately to the subject. 20 Therefore, the methods of the invention comprises further administering a cytokine. While the compounds of the invention may be used with or without further administration, in a preferred aspect a cytokine can be administered, wherein said cytokine is capable of increasing the expansion of a y8 T cell population treated with an angelyl or tiglyl phosphoester compound, preferably 25 wherein the cytokine is capable of inducing an expansion of a y78 T cell population which is greater than the expansion resulting from administration of the angelyl or tiglyl phosphoester compound in the absence of said cytokine. A preferred cytokine is an interleukin-2 polypeptide. A cytokine having y 8 T cell proliferation inducing activity, most preferably the interleukin-2 30 polypeptide, is administered at low doses, typically over a period of time comprised between 1 and 10 days. The angelyl phosphoester is preferably administered in a single dose, and typically at the beginning of a cycle. Preferably, the interleukin-2 polypeptide is administered at a daily dose comprised between 0.2 and 2 MU per day, even more preferably between 0.2 and 1.5 MU, further preferably between 0.2 and 1 MU. The daily dose of cytokine, preferably an interleukin-2 35 polypeptide, is administered as a single injection or in two injections.

WO 2006/103568 PCT/IB2006/001206 39 In preferred aspects, a cytokine, most preferably 1L-2, is administered daily for up to about 10 days, preferably for a period of between about 3 and 10 days, or most preferably for about 7 days. Preferably, the administration of the cytokine begins on the same day (e.g. within 24 hours of) as administration of the y8 T cell activator. For example, in one aspect the cytokine is administered 5 each day, while in other aspects the cytokine need not be administered on each day. When the cytokine is administered for about 7 to about 14 days, a 4-weekly treatment cycle is preferred. When the first component is administered for about 4 days, a 3-weekly day treatment cycle is preferred. In preferred embodiments, the compounds can be used according to any of the methods described in International Patent Application number WO2004050096, the disclosure of which is 10 incorporated herein by reference. The above methods and treatments may be used alone or in combination with other active agents or treatments. For instance, for the treatment of tumors, the invention may be used in combination with other anti-tumor agents or treatments, such as chemotherapy, radiotherapy or gene therapy. 15 The invention also relates to a product comprising an angelyl or tiglyl phosphoester according to the present invention and an interleukin-2 polypeptide, for separate use, for regulating the activity of y8 T cells in a mammalian subject. 20 The invention concerns a vaccinal composition comprising an angelyl or tiglyl phosphoester according to the present invention. The invention also concerns the use of an angelyl or tiglyl phosphoester according to the present invention as a vaccine adjuvant. Accordingly, the present invention discloses methods and compositions for enhancing and/or 25 augmenting the immune response against an antigen in a mammal, notably a human, involving the conjoint immunization of the mammal with (i) a composition comprising an antigen and (ii) an adjuvant comprising an angelyl or tiglyl phosphoester compound according to the present invention. Preferably said composition comprising an antigen comprises a killed, inactivated or attenuated pathogen, microorganism or parasite. In other aspect, said composition comprising an 30 antigen preferably comprises an enriched or purified polypeptide, lipid, polysaccharide, glycoprotein, glycolipid or nucleic acid antigen. Preferably said composition comprises at least 1, 2, 3, 4, 5, 10 or 15 distinct antigens, for example at least 1, 2, 3, 4, 5, 10 or 15 distinct polypeptides, or nuclei acids encoding such polypeptides. In preferred embodiments, the compounds can be used as described in U.S. Provisional Patent Application number 60/564,959, filed April 26 t , 2004, the 35 disclosure of which is incorporated herein by reference.

WO 2006/103568 PCT/IB2006/001206 40 The adjuvant composition will comprise an effective amount of an angelyl or tiglyl phosphoester compound according to the present invention, said amount being an effective amount allowing the elicitation of a humoral response, elicitation of a cytotoxic T lymphocyte (CTL) response, or elicitation of both a humoral response and a CTL response of the adjuvant composition with 5 respect to at least one antigen. Preferably the angelyl or tiglyl phosphoester compound according to the present invention, is present in an amount effective to produce a greater immunological effect in eliciting a humoral response, a cytotoxic T lymphocyte (CTL) response or both a humoral response and a CTL response when administered conjointly with an antigen than that immunological effect produced when said antigen is administered in the absence of the adjuvant. 10 The antigen component of the composition can be selected from virtually any antigen, antigenic determinant or hapten of medical or veterinary interest, and particularly for those antigens for which an increase in immunogenicity is desired. 15 Therefore, the present invention concerns the use of an angelyl or tiglyl phosphoester compound according to the present invention, more preferably the compounds of Formulas I to XV, as a vaccine adjuvant. The present invention further concerns a vaccine composition comprising an antigen or a combination of antigens, and an angelyl or tiglyl phosphoester compound according to the present invention, more preferably the compounds of Formulas I to XV. Preferably, said 20 composition comprises a therapeutically effective amount of antigen and an immune response enhancing or immune response augmenting amount of the angelyl or tiglyl phosphoester. Preferably, said vaccine composition prevents a microbial infection. Said microbial infection is caused by a microbe selected from the group consisting of viruses, fungi, parasites, yeast, bacteria, and protozoa. In a particular embodiment, said vaccine composition is BCG vaccine composition. 25 Alternatively, said vaccine composition prevents or is a treatment against a tumor. The present invention further concerns a vaccine kit comprising a suitable container containing a vaccine composition according to the present invention, more particularly comprising an antigen or a combination of antigens, and an angelyl or tiglyl phosphoester compound according to the 30 present invention, more preferably the compounds of Formulas I to XV. Optionally, said vaccine can comprise two separate suitable containers, one containing the antigen or the combination of antigens and the other containing an angelyl or tiglyl phosphoester compound according to the present invention, more preferably the compounds of Formulas I to XV. Optionally, said container can be a syringue. Alternatively, said vaccine kit comprises one or two containers and a syringue. 35 WO 2006/103568 PCT/IB2006/001206 41 The present invention concerns a method of improving the potency of a vaccine in a subject, or of immunizing a subject against a disease, more particularly a microbial infection, comprising the steps of: administering to said subject a composition comprising an antigen or a combination of 5 antigens; and, conjointly administering to said subject an angelyl or tiglyl phosphoester compound according to the present invention, more preferably the compounds of Formulas I to XV, more particularly an immune response enhancing amount thereof. Preferably, the angelyl or tiglyl phosphoester compound according to the present invention, when administered conjointly with a 10 composition comprising an antigen, is administered in an amount sufficient to enhance an immune response over that observed with said composition comprising an antigen in the absence of the angelyl phosphoester. Preferably said composition comprising an antigen comprises a killed, inactivated or attenuated pathogen, microorganism or parasite. In other aspect, said composition comprising an antigen preferably comprises an enriched or purified polypeptide, lipid, 15 polysaccharide, glycoprotein, glycolipid or nucleic acid antigen. The present invention also concerns a method of immunizing a subject against a disease, more particularly a microbial infection, in a subject comprising administering to said subject (i) a composition comprising an antigen, and (ii) an angelyl or tiglyl phosphoester compound according 20 to the present invention, more preferably Formulas I to XV. Preferably the angelyl or tiglyl phosphoester compound according to the present invention is administered in an immune response enhancing amount. Preferably the angelyl or tiglyl phosphoester and the composition comprising an antigen are administered as a single vaccine composition in a therapeutically effective amount. 25 Preferably, said angelyl or tiglyl phosphoester is provided or administered together with a pharmaceutically acceptable carrier. In a first aspect, said administrations of said antigen or combination of antigens and said angelyl or tiglyl phosphoester are simultaneously. In a second aspect, said administrations of said antigen or combination of antigens and said angelyl or tiglyl phosphoester are administered sequentially. More particularly, said angelyl or tiglyl phosphoester 30 can be administered prior to, concurrently with or subsequent to administration of an antigen or a combination of antigens to a subject for immunization purposes. Preferably, said antigen or combination of antigens are microbial antigens, preferably, viral, bacterial, fungal, protozoan, yeast or parasite antigens. In a preferred embodiment, said antigen is a antigen of Mycobacterium bovis. Optionally, said antigen or combination of antigens is a tumoral antigen. 35 Further aspects and advantages of this invention will be disclosed in the following examples, which should be regarded as illustrative and not limiting the scope of this application.

WO 2006/103568 PCT/IB2006/001206 42 EXAMPLES Example 1 5 Synthesis of (E)-4-hydroxy-2-methyl-but-2-envl DVyroDhosphate (Hydroxvtiglvl pyrophosphate or HTiglvlPP) The synthesis of HTiglylPP was carried out according to the scheme presented in Figure 1 starting from commercially available 2-methyl-2-vinyloxirane. 10 Preparation of (E)-4-Chloro-2-methylbut-2-en- 1-ol: 16 ml (179 mmol) of TiCl 4 was added under nitrogen to 360 ml of CH 2

C

2 . The solution was cooled to 90 0 C and a solution of 10.0 g (119 mmol) of 2-methyl-2-vinyloxirane in 50 ml of

CH

2 C1 2 was added dropwise keeping the temperature below -80 0 C. The red solution was then 15 stirred at 80 0 C for 2 hours and quenched with 600 ml of IM HC1. The organic phase was separated and the aqueous phase was extracted with 3x500 ml of Et 2 0. The combined organic phases were dried over MgSO 4 , filtered and evaporated at 350 mbar at 25 0 C to give 12.02 g (99.7 mmol, 84% yield) of 4-Chloro-2-methylbut-2-en-1-ol as brownish oil. The crude product was directly used in the next step. 20 Preparation of (E)-2-(4-Chloro-2-methylbut-2-en yloxv)tetrahydro-2H-pvran: To a solution of 11.5 g (95.37 mmol) of 4-Chloro-2-methylbut-2-en-1-ol in 120 ml of CH 2 0 2 was added 26 ml (286.11 mmol) of Dihydropyrane (DHP). The solution was cooled at 0oC and 2.4 g (9.53 mmol) of pyridinium p-toluene sulfonate (PPTS) was added portion wise. The solution was 25 stirred for 3 hours at 0oC. The organic phase was washed with 3x50 ml of water, dried over Na 2

SO

4 , filtered and concentrated to give the crude product. The product was then purified by chromatography on silica gel using heptane/EtOAc (9/1) as eluent. 12.35 g (60.33 mmol, 64 % yield) of the protected allylic alcohol were isolated as colorless oil. 30 Preparation of (E)-3-methyl-4-(tetrahydro-2H-pran-2-yloxy)but-2-enyl acetate: To a solution of 1.0 g (5 mmol) of the protected allylic alcohol (E)-2-(4-Chloro-2-methylbut-2-en yloxy)tetrahydro-2H-pyran in 30 ml of DMF was added 820 mg (10 mmol) of sodium acetate followed by a catalytic amount of Nal (20 mg). The reaction mixture was heated at 80 0 C for 6 hours. The reaction mixture was cooled and poured onto 200 ml of water. The solution was 35 extracted with 3x50 ml of EtOAc. The combined organic phases were dried over Na2SO4, filtered and concentrated to give the crude product. This product was then purified by chromatography on WO 2006/103568 PCT/IB2006/001206 43 silica gel using Heptane/EtOAc (8/2) as eluent. 463 mg (2.03 mmol, 40 %) of (E)-3-methyl-4 (tetrahydro-2H-pyran-2-yloxy)but-2-enyl acetate were isolated as colour less oil. Preparation of (E)-4-bromo-3-methylbut-2-enyl acetate: 5 To a solution of 460 mg (2.0 mmol) of (E)-3-methyl-4-(tetrahydro-2H-pyran-2-yloxy)but-2-enyl acetate in 20 ml of CH 2 C1 2 was added a solution of 1.33 g (4 mmol) of CBr 4 in 10 ml of CH 2 Cl 2 . The solution was cooled to 0oC and a solution of 1.05 g (4 mmol) oftriphenylphosphine was added dropwise. The solution was allowed to warm up to room temperature for 6 hours and stirred at the same temperature for further 1 hour. The precipitate was filtered and the filtrate was evaporated. 10 The residue was purified by chromatography on silica gel using Heptane /EtOAc (8/2) as eluent. 314 mg (1.52 mmol, 76 %) of (E)-4-bromo-3-methylbut-2-enyl acetate were isolated as colourless oil. Preparation of (E)-4-hydroxy-2-methylbut-2-envl pyrophosphate: 15 A solution of 900 mg (4.35 mmol) of (E)-4-bromo-3-methylbut-2-enyl acetate in 10 ml of

CH

3 CN was added dropwise to a solution of 5.9 g (6.52 mmol) of TTAPP in 15 ml of CH 3 CN. The reaction mixture was stirred at room temperature overnight and the solvent was evaporated. The residue was then passed through Dowex 50WX8 (NH4 form) resin column and eluted with 2 volumes of 40 mM of NHI 4

HCO

3 aqueous solution. The fraction was evaporated under high 20 vacuum at 40-45 0 C. The residue was stirred with 4-5 ml of iPrOH/NH 4 OH 28 % (1/1) and the unsoluble solid was filtered off. The filtrate was chromatographied on silica gel using iPrOH/NH4OH 28% 1/1) as eluent. 197 mg (0.752 mmol, 17 %) of (E)-4-hydroxy-2-methylbut-2 enyl pyrophosphate, ammonium salt were isolated as a white solid. Under these conditions, the deprotection of the acetate moiety (alcohol protecting group) took place while chromatography on 25 silica gel. The isomeric ratio (E:Z) in the purified product was 96:4 on the basis of Ionic Chromatography (HPAEC) analysis. Each E and Z stereoisomer of 4-hydroxy-2-methylbut-2-enyl pyrophosphate was obtained as a pure compound by chromatographic purification (HPAEC) through lonPac® AS11 column, with 30 multiple chromatographic passes being combined. For the purpose of performing biological testing, neutral aqueous solutions of the product was sterilized by filtration through 0.2 gm filter and stored at -20 0 C. In the case of testing performed in vivo the solutions are passed beforehand through a DOWEX 50WX8-200 cationic resin column 35 (Na' form) eluted by two column volumes of deionized water.

WO 2006/103568 PCT/IB2006/001206 44 Example 2 Synthesis of (Z)-4-hydroxy-2-methyl-but-2-enyl pyrophosphate (Hydroxvan2elvl pyrophosphate or HAngelvlPP) 5 The synthesis of (Z)-4-hydroxy-2-methylbut-2-enyl pyrophosphate (HAngelylPP) is carried out according to the scheme illustrated in Figure 2 starting from commercially available TBDMS protected propargyl alcohol. For each step of this synthetic scheme the following references may be used for further guidance: 10 Step a (propargyl ester formation from methyl chloroformate): Andrew T. Koppisch et al, Organic Letters, Vol. 2 No. 2 (2000) p215-217; Michael S. Leonard and al, J Org. Chem. (2004), 69, 2526 253 1; Step b (stereoselective conjugate addition of dimethylcopper-lithium reagent to the o,3 acetylenic ester): E. J. Corey and John A. Katzenellenbogen, J. Am. Chem. Soc. (1969), 91, 1851-1852; 15 Andrew T. Koppissch et al, Organic Letters, Vol. 2 No. 2 (2000) p215-217; Michael S. Leonard and al, J. Org. Chem. (2004), 69, 2526-2531; Step c (ester reduction with DIBAL hydride): Andrew T. Koppisch et al, Organic Letters, Vol. 2 No. 2 (2000) p215-217; Michael S. Leonard et al, J. Org. Chem. (2004), 69, 2526-2531; Step d: the allylic alcohol is converted into a THP-protected form by reaction with dihydropyrane 20 (DHP) following the procedure reported in example 1 or as described by Miyashita et al (Miyashita et al, J. Org. Chem. 42 (1977) 3772-3774); Step e: (non acidic cleavage of the t-butyldimethylsilyl protective group): E. J. Corey and A. Venkateswarlu, J. Am. Chem. Soc. (1972), 94, 6190; alternative conditions for this deprotection reaction can also be found in "Protective Groups in Organic Synthesis", Third Edition, Theodora 25 W. Greene and Peter G. M. Wuts, published by John Wiley & Sons, Inc. (1999); Step f (chlorination step): in a standard procedure, triethylamine is added to a solution of the allylic alcohol in CH 2

C

2 at 25 0 C. The resulting clear reaction mixture is then treated by the dropwise addition ofmesyl chloride during 20 min. After complete addition, the reaction mixture is stirred at room temperature for at least 1.5 hours until complete conversion. The reaction mixture is 30 washed successively with saturated aqueous NaHCO 3 solution, 0.1 M aqueous HC1 and deionized water then concentrated under reduced pressure. The crude product is purified by chromatography using SiO 2 and an elution solvent of ethyl acetate : heptane = 1 : 9; Step g: the pyrophosphorylation of the THP-protected angelyl chloride with Tris tetra-n butylammonium hydrogen diphosphate (TTAPP) is achieved following the general procedure 35 reported by Poulter and co-workers (David T. Fox and C. Dale Poulter, J. Org. Chem.(2002), 67, 5009-5010; Davisson V. J. et al., J. Org. Chem., 1986, 51, p 4768-4779. Deprotection of the tetrahydropyranyl group is achieved by treatment of the pyrophosphate ester with DOWEX WO 2006/103568 PCT/IB2006/001206 45 50WX8 (WJ form) cation exchange resin and subsequent neutralization of the resulting acidic solution with ammonium hydroxide. For the purpose of performing biological testing, neutral aqueous solutions of the product is 5 sterilized by filtration through 0.2 Lm filter and stored at -20 0 C. In the case of testing performed in vivo the solutions are passed beforehand through a DOWEX 50WX8-200 cationic resin column (Na + form) eluted by two column volumes of deionized water. Example 3 10 Synthesis of (Z)-5-hydroxy-3-methylpent-3-envl pyrophosphonate (Hydroxvaneelvl pyrophosphonate or C-IHAngelvlPP) The synthesis of (Z)-5-hydroxy-3-methylpent-3-enyl pyrophosphonate (C-HAngelylPP) is performed according to the scheme illustrated in Figure 2 from the THP-protected 15 chloromethylbutenyl intermediate (product of step f) whose preparation is described in exemple 1. Chemical reactions of step h and step i involving coupling of the pyrophosphonate moiety is carried out following the procedure of Valentijn et al for the preparation of Farnesyl Pyrophosphate analogues (Valentijn et al, Synlett (1991) 663-664): 20 Step i: The phosphonylating agent (methyl methylphosphonomorpholidate) is prepared by treatment of commercially available methylphosphonic dichloride with morpholine and methanol. The coupling 25 product is obtained by reaction of the THP-protected chloromethylbutenyl intermediate with methyl lithiomethylphosphonomorpholidate prepared in situ from the phosphonylating agent and n butyl lithium in THF. Step h: 30 A crude solution of C-HAngelylPP is obtained in a 3-step procedure: 1) Demethylation (hydrolysis) of the product of step i by treatment with tetra-n butylammonium hydroxide in methanol as described by Phan and Poulter, J. Org. Chem. (2001), 66, 6705-6710, 35 2) Pyrophosphorylation with phosphoric acid (as tributylammonium salt) following the method of Valentijn et al, 3) Deprotection of the tetrahydropyranyl group by treatment of the pyrophosphonate ester with DOWEX 50WX8 (I form) cation exchange resin and subsequent neutralization of the resulting acidic solution with ammonium hydroxide.

WO 2006/103568 PCT/IB2006/001206 46 Purification of the resulting crude solution is performed by chromatography over silica gel using 25 % ammonia solution/2-propanol 50/50 (v/v) as eluant. For the purpose of performing biological testing, the aqueous solutions of the product are sterilized by filtration through a 0.2 pLm filter and 5 stored at -20 oC. In the case of testing performed in vivo, the solutions are passed beforehand through a DOWEX 50WX8-200 cationic resin column (sodium form) eluted by two column volumes of deionized water. Example 4 10 Dosage response for IHIAngelylPP and HItiglyvlPP compounds Cytokine release assay Cells (primary polyclonal human Vy9V82 T cells which have been expanded in vitro and stored frozen at day 12-15 of expansion) are thawed and rinsed twice and centrifuged. Upon elimination 15 of supernatant and resuspension of cells, the cells are incubated for 24h at 37 0 C in the presence of IL2 100 IU/ml (final concentration). The cells are washed and centrifuged, following which the supernatant is eliminated and the cells are resuspended and adjusted to the adequate final concentration. The cells are added to the wells of a 96-well plate. 20 To one row of wells is added a standard dilution series of (R,S)-3-(bromomethyl)-3-butanol-l-yl diphosphate (R,S-BrHPP). Compounds to be tested, in this case (E)-4-hydroxy-3-methyl-2-butenyl pyrophosphate ((E)-HDMAPP) and the HAngelylPP and HTiglylPP compounds of the Angelyl/Tiglyl phosphoester series are added to experimental wells, after several dilutions. 25 Full plates are incubated 24 hours at 37 0 C for stimulation of the y8 cells with the test compound and reference compounds, in this case HAngelylPP and HTiglylPP, (R,S)-BrHPP and (E) HDMAPP, as further described below. After this time, 100 jil of culture supernatant is taken for TNFu dosage. Measurement of the released TNFu dosage is performed as described by the manufacturer's instruction in the TNFc enzyme immunoassay kit (ref. 11121, Immunotech 30 Beckman Coulter). OD at 405nm is read, the OD being proportional to the concentration of released TNFu in the culture supernatant. The data are processed with the Excel software to compare concentration of test compound versus concentration of TNF and for the calculation of the EC50 for each test compound. 35 IHAngelylPP in vitro bioactivity The bioactivity of the compound HAngelylPP was assessed using a TNFa release assay as described above. In vitro activity is shown in Figure 3. Compounds (R,S)-BrHPP and (E)- WO 2006/103568 PCT/IB2006/001206 47 HDMAPP were included for purpose of comparison. The in vitro EC50 was then assessed in this in vitro relative screening test, where prior assays with calibrated cells using a (R,S)-BrHPP-standard composition presented an EC50 of about 15 nM for the reference (R,S)-BrHPP compound. As will be appreciated, any other suitable assays such as cell amplification may be used in assessing 5 compounds. The in vitro EC50 for HAngelylPP (Z isomer) was determined to be 0.85 nM and for HTiglylPP (E isomer) was 15 nM, while the in vitro EC50 for (E)-HDMAPP was 2.1 nM and the in vitro EC50 for (R,S)-BrHPP was 37.7 nM. Since the assay provides a relative result rather than absolute EC50 value, the results indicate that both HAngelylPP and HTiglylPP compounds are highly potent, and that the Z isomer (HAngelylPP) is the most potent compound of those tested. 10 REFERENCES All the cited references are incorporated herein by reference. Azzi, A., Casey, R.P. & Nalecz, M. (1984) The effect of N,N'-dicyclohexylcarbodiimide on enzymes of bioenergetic relevance. Biochim. Biophys. Acta, 768(3-4):209-226 15 Bank, I., Book, M., Huszar, M., Baram, Y., Schnirer, I., and Brenner, H. (1993). V delta 2+ gamma delta T lymphocytes are cytotoxic to the MCF 7 breast carcinoma cell line and can be detected among the T cells that infiltrate breast tumors. Clin Immunol Immunopathol 67, 17-24. Behr, C., Poupot, R., Peyrat, M. A., Poquet, Y., Constant, P., Dubois, P., Bonneville, M., and Fournie, J. J. (1996). Plasmodium falciparum stimuli for human gammadelta T cells are related to 20 phosphorylated antigens of mycobacteria. Infect Immun 64, 2892-2896. Belmant, C., Espinosa, E., Halary, F., Tang, Y., Peyrat, M. A., Sicard, H., Kozikowski, A., Buelow, R., Poupot, R., Bonneville, M., and Fournie, J. J. (2000). A chemical basis for selective recognition of nonpeptide antigens by human delta T cells. Faseb J 14, 1669-1670. Bukowski, J. F., Morita, C. T., Tanaka, Y., Bloom, B. R., Brenner, M. B., and Band, H. (1995). V 25 gamma 2V delta 2 TCR-dependent recognition of non-peptide antigens and Daudi cells analyzed by TCR gene transfer. J Immunol 154, 998-1006. Burton D.J., and Sprague, L.G. (1989). Allylations of [(Diethoxyphosphinyl)difluromethyl]zine Bromide as a convenient route of 1,1-Difluoro-3-alkenephosphonates. J. Org. Chem. 54, 613-617. Choudhary, A., Davodeau, F., Moreau, A., Peyrat, M. A., Bonneville, M., and Jotereau, F. (1995). 30 Selective lysis of autologous tumor cells by recurrent gamma delta tumor-infiltrating lymphocytes from renal carcinoma. J Immunol 154, 3932-3940. Chu, B.C.F., Wahl, G. M.and Orgel, L.E/, NucleidAcids Research, Vol 11, No 18 (1983). Constant, P., Poquet, Y., Peyrat, M. A., Davodeau, F., Bonneville, M., and Fournie, J. J. (1995). The antituberculous Mycobacterium bovis BCG vaccine is an attenuated mycobacterial producer of 35 phosphorylated nonpeptidic antigens for human gamma delta T cells. Infect Immun 63, 4628-4633. Corey E.J. and Katzenellenbogen J.A., J. Am. Chem. Soc. (1969), 91, 1851-1852 Corey E. J. and A. Venkateswarlu, J. Am. Chem. Soc. (1972), 94, 6190 WO 2006/103568 PCT/IB2006/001206 48 Cox R. J., Gibson J. S., Mayo Martin M. B., Chem BioChem, 2002, 3, 874-886 Davisson et al., Methods Enzymol., 1984, 110, p 130-145. Davisson et al., J. Org. Chem., 1986, 51, p 4768-4779. Davisson et al., J. Org. Chem., 1987, 52, p 1794-1801. 5 Davodeau et al, (1993) J. Immunology 151(3): 1214-1223) Espinosa, E., Belmant, C., Pont, F., Luciani, B., Poupot, R., Romagne, F., Brailly, H., Bonneville, M., and Fournie, J. J. (2001a). Chemical synthesis and biological activity of bromohydrin pyrophosphate, a potent stimulator of human gamma delta T cells. J Biol Chem 276, 18337-18344. Espinosa, E., Belmant, C., Sicard, H., Poupot, R., Bonneville, M., and Fournie, J. J. (2001b). 10 Y2K+1 state-of-the-art on non-peptide phosphoantigens, a novel category of immunostimulatory molecules. Microbes Infect 3, 645-654. Ferrarini, M., Heltai, S., Pupa, S. M., Mernard, S., and Zocchi, R. (1996). Killing of laminin receptor-positive human lung cancers by tumor infiltrating lymphocytes bearing gammadelta(+) t cell receptors. J Natl Cancer Inst 88, 436-441. 15 Feurle, J., Espinosa, E., Eckstein, S., Pont, F., Kunzmann, V., Fournie, J. J., Herderich, M., and Wilhelm, M. (2002). Escherichia coli produces phosphoantigens activating human gamma delta T cells. J Biol Chem 277, 148-154. Fisch, P., Moris, A., Rammensee, H. G., and Handgretinger, R. (2000). Inhibitory MHC class I receptors on gammadelta T cells in tumour immunity and autoimmunity. Immunol Today 21, 187 20 191. Fournie, J. J., and Bonneville, M. (1996). Stimulation of gamma delta T cells by phosphoantigens. Res Immunol, 66 th Forum in Immunology, 147, 338-347. Fox D.T. and Poulter C. D., J Org. Chem.(2002), 67, 5009-5010 Fujimiya, Y., Suzuki, Y., Katakura, R., Miyagi, T., Yamaguchi, T., Yoshimoto, T., and Ebina, T. 25 (1997). In vitro interleukin 12 activation of peripheral blood CD3(+)CD56(+) and CD3(+)CD56(-) gammadelta T cells from glioblastoma patients. Clin Cancer Res 3, 633-643. Gober, H. J., Kistowska, M., Angman, L., Jeno, P., Mori, L., and De Libero, G. (2003). Human T cell receptor gammadelta cells recognize endogenous mevalonate metabolites in tumor cells. J Exp Med 197, 163-168. 30 Hayday, A. C. (2000). [gamma] [delta] cells: a right time and a right place for a conserved third way of protection. Annu Rev Immunol 18, 975-1026. Hintz et al. (2001). Identification of (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate as a major activator for human gammadelta T cells in Escherichia coli. FEBS Lett. 509(2):317-22 Jomaa, H., Feurle, J., Luhs, K., Kunzmann, V., Tony, H. P., Herderich, M., and Wilhelm, M. 35 (1999a). Vgamma9/Vdelta2 T cell activation induced by bacterial low molecular mass compounds depends on the 1-deoxy-D-xylulose 5-phosphate pathway of isoprenoid biosynthesis. FEMS Immunol Med Microbiol 25, 371-378.

WO 2006/103568 PCT/IB2006/001206 49 Jomaa, H., Wiesner, J., Sanderbrand, S., Altincicek, B., Weidemeyer, C., Hintz, M., Turbachova, I., Eberl, M., Zeidler, J., Lichtenthaler, H. K., et al. (1999b). Inhibitors of the nonmevalonate pathway of isoprenoid biosynthesis as antimalarial drugs. Science 285, 1573-1576 Kato, Y., Tanaka, Y., Miyagawa, F., Yamashita, S., and Minato, N. (2001). Targeting of tumor 5 cells for human gammadelta T cells by nonpeptide antigens. J Immunol 167, 5092-5098. Knorre et al., Febs letters, 1976, 70, 105-108. Kobayashi, H., Tanaka, Y., Yagi, J., Toma, H., and Uchiyama, T. (2001). Gamma/delta T cells provide innate immunity against renal cell carcinoma. Cancer Immunol Immunother 50, 115-124 Koppisch A.T. et al, Organic Letters, Vol. 2 No. 2 (2000) p215-217 10 E.M. Kosower, B. Pazhenchevsky, H. Dodiuk, H. Kanety, and D. Faust, J. Org. Chem., 46, 1668 (1981) Kunzmann, V., Bauer, E., and Wilhelm, M. (1999). Gamma/delta T-cell stimulation by pamidronate. N Engl J Med 340, 737-738. Lang, F., Peyrat, M. A., Constant, P., Davodeau, F., David-Ameline, J., Poquet, Y., Vie, H., 15 Fournie, J. J., and Bonneville, M. (1995). Early activation of human V gamma 9V delta 2 T cell broad cytotoxicity and TNF production by nonpeptidic mycobacterial ligands. J Immunol 154, 5986-5994. Leonard M. S. and al, J Org. Chem. (2004), 69, 2526-2531 Liu et al., Angew. Chem. Int. Ed. 1999, 38, No 9, p 1245-1247. 20 Mitropoulos, D., Kooi, S., Rodriguez-Villanueva, J., and Platsoucas, C. D. (1994). Characterization of fresh (uncultured) tumour-infiltrating lymphocytes (TIL) and TIL-derived T cell lines from patients with renal cell carcinoma. Clin Exp Immunol 97, 321-327. Miyashita et al, J. Org. Chem. 42 (1977) 3772-3774) Miyagawa, F., Tanaka, Y., Yamashita, S., and Minato, N. (2001). Essential requirement of antigen 25 presentation by monocyte lineage cells for the activation of primary human gamma delta T cells by aminobisphosphonate antigen. J Immunol 166, 5508-5514. Moreau et al, (1986) J. Clin. Invest. 78:874) Morita, C. T., Beckman, E. M., Bukowski, J. F., Tanaka, Y., Band, H., Bloom, B. R., Golan, D. E., and Brenner, M. B. (1995). Direct presentation of nonpeptide prenyl pyrophosphate antigens to 30 human gamma delta T cells. Immunity 3, 495-507. Nikolaides et al, Conversion Of Amines To Phosphoesters: Decyl Diethyl Phosphate, Organic Syntheses, CV 9, 194 Nilsson et al., Acta Chemica Scandinavia B 35, 1981, p 19-27. Nilsson and Mosbach, Eur. J. Biochem., 1980, vol. 112, p 397-402. 35 Phan and Poulter, J. Org. Chem. (2001), 66, 6705-6710 Poccia, F., Cipriani, B., Vendetti, S., Colizzi, V., Poquet, Y., Battistini, L., Lopez-Botet, M., Fournie, J. J., and Gougeon, M. L. (1997a). CD94/NKG2 inhibitory receptor complex modulates WO 2006/103568 PCT/IB2006/001206 50 both anti-viral and anti-tumoral responses of polyclonal phosphoantigen-reactive V gamma 9V delta 2 T lymphocytes. J Immunol 159, 6009-6017. Poccia, F., Malkovsky, M., Gougeon, M. L., Bonneville, M., Lopez-Botet, M., Fournie, J. J., and Colizzi, V. (1997b). Gammadelta T cell activation or anergy during infections: the role of 5 nonpeptidic TCR ligands and HLA class I molecules. J Leukoc Biol 62, 287-291. Poquet, Y., Kroca, M., Halary, F., Stenmark, S., Peyrat, M. A., Bonneville, M., Fournie, J. J., and Sjostedt, A. (1998). Expansion of Vgamma9 Vdelta2 T cells is triggered by Francisella tularensis derived phosphoantigens in tularemia but not after tularemia vaccination. Infect Immun 66, 2107 2114. 10 Rohmer, M., Knani, M., Simonin, P., Sutter, B., and Sahm, H. (1993). Isoprenoid biosynthesis in bacteria: a novel pathway for the early steps leading to isopentenyl diphosphate. Biochem J 295 ( Pt 2), 517-524. Rojas, R. E., Torres, M., Fournie, J. J., Harding, C. V., and Boom, W. H. (2002). Phosphoantigen presentation by macrophages to mycobacterium tuberculosis--reactive Vgamma9Vdelta2+ T cells: 15 modulation by chloroquine. Infect Immun 70, 4019-4027. Sato, E., Yoshikawa, M., and Kanaoka, Y. Chem. Pharm. Bull, 38(8), 2287-2289 (1990) Seghal, D, Vijay, I.K., Anal Biochem, 218, 87 (1994) Selin, L. K., Stewart, S., Shen, C., Mao, H. Q., and Wilkins, J. A. (1992). Reactivity of gamma delta T cells induced by the tumour cell line RPMI 8226: functional heterogeneity of clonal 20 populations and role of GroEL heat shock proteins. Scand J Immunol 36, 107-117. Shen, Y., Zhou, D., Qiu, L., Lai, X., Simon, M., Shen, L., Kou, Z., Wang, Q., Jiang, L., Estep, J., et al. (2002). Adaptive immune response of Vgamma2Vdelta2+ T cells during mycobacterial infections. Science 295, 2255-2258. Sicard, H., Al Saati, T., Delsol, G., and Fournie, J. J. (2001). Synthetic phosphoantigens enhance 25 human Vgamma9Vdelta2 T lymphocytes killing of non-Hodgkin's B lymphoma. Mol Med 7, 711 722. Sturm, E., Braakman, E., Fisch, P., Vreugdenhil, R. J., Sondel, P., and Bolhuis, R. L. (1990). Human V gamma 9-V delta 2 T cell receptor-gamma delta lymphocytes show specificity to Daudi Burkitt's lymphoma cells. J Immunol 145, 3202-3208. 30 Tanaka, Y., Morita, C. T., Nieves, E., Brenner, M. B., and Bloom, B. R. (1995). Natural and synthetic non-peptide antigens recognized by human gamma delta T cells. Nature 375, 155-158. Theodora W. Greene and Peter G. M. Wuts, "Protective Groups in Organic Synthesis", Third Edition, published by John Wiley & Sons, Inc. (1999) Valentijn; van der Marel; Cohen; van Boom, Syn. lett. 1991, 663-664. 35 Valentijn, A. R. P. M.; O. van der Berg, G. A. van der Marel; L. H. Cohen; J. H. van Boom, Tetrahedron, vol. 51-7, 1995, 2099-2108.

WO 2006/103568 PCT/IB2006/001206 51 Waschbusch et al. (1997). A new route to alpha-fluoroalkylphosphonates. J. Chem. Soc. Perkin Trans. 1, 1135-1139. Wilhelm, M., Kunzmann, V., Eckstein, S., Reimer, P., Weissinger, F., Ruediger, T., and Tony, H. P. (2003). {gamma} {delta} T cells for immune therapy of patients with lymphoid malignancies. 5 Blood, 102(1), 200-6. Yamaguchi, T., Fujimiya, Y., Suzuki, Y., Katakura, R., and Ebina, T. (1997). A simple method for the propagation and purification of gamma delta T cells from the peripheral blood of glioblastoma patients using solid-phase anti-CD3 antibody and soluble IL-2. J Immunol Methods 205, 19-28. Zhang Donglu and Poulter C. Dale "Analysis and Purification of Phosphorylated Isoprenoids by 10 Reversed-Phase HPLC", Analytical Biochemistry, vol. 213, 356-361 (1993) Zheng, B., Lam, C., Im, S., Huang, J., Luk, W., Lau, S. Y., Yau, K. K., Wong, C., Yao, K., and Ng, M. H. (2001 a). Distinct tumour specificity and IL-7 requirements of CD56(-)and CD56(+) subsets of human gamma delta T cells. Scand J Immunol 53, 40-48. Zheng, B. J., Chan, K. W., Im, S., Chua, D., Sham, J. S., Tin, P. C., He, Z. M., and Ng, M. H. 15 (200 1 b). Anti-tumor effects of human peripheral gammadelta T cells in a mouse tumor model. Int J Cancer 92, 421-425.

Claims (30)

1. A 78 T cell activator of formula (I): R 3 0 0 R 5 -W=C-C-A--P-B- -- Y I I I R 7 R 4 OCat+ O-Cat + m (I) 5 wherein Cat+ represents one (or several, identical or different) organic or mineral cation(s) (including proton); m is an integer from 1 to 3; B is O, NH, or any other group capable of being hydrolyzed; A is O, NH, CHF, CF 2 or CH 2 , or any other isosteric group; 10 W is C-R 6 orN; R 7 is a (C 1 -C 3 )alkyl group or a (CI-C 3 )alkyl group or any other isosteric group such as CF 3 ; R 3 , R4, and R 6 , identical or different, are a hydrogen or a (Cx-C 3 )alkyl group or any other isosteric group such as CF 3 ; R5 is an (C 2 -C 3 )acyl, an aldehyde, an (C 1 -C 3 )alcohol, or an (C 2 -C 3 )ester; and, 15 Y = O-Cat+, a C 1 -C 3 alkyl group, a group -A-R, wherein R is a linear, branched, or cyclic, aromatic or not, saturated or unsaturated, C 1 -C 5 0 hydrocarbon group, optionally interrupted by at least one heteroatom, wherein said hydrocarbon group comprises an alkyl, an alkylenyl, or an alkynyl, preferably an alkyl or an alkylene, which can be substituted by one or several substituents selected from the group consisting of: an alkyl, an alkylenyl, an alkynyl, an epoxyalkyl, an aryl, an 20 heterocycle, an alkoxy, an acyl, an alcohol, a carboxylic group (-COOH), an ester, an amine, an amino group (-NH 2 ), an amide (-CONH 2 ), an imine, a nitrile, an hydroxyl (-OH), a aldehyde group (-CHO), an halogen, an halogenoalkyl, a thiol (-SH), a thioalkyl, a sulfone, a sulfoxide, and a combination thereof; and wherein the group R5 and the moiety -CR 3 R4-A-[POOB]m-POOY of formula (II) are in 25 Z (or cis) configuration. 30 WO 2006/103568 PCT/IB2006/001206 53

2. The y8 T cell activator according to claim 1, wherein said activator is a compound of formula (II): R6 R 3 O O C C-C-A- -P-B--P-Y R7 R4 O-Cat+ O-Cat+ m ( II), wherein Cat+, m, B, A, Rs, R 3 , R 4 , R 6 , R 7 , and Y have the same meaning as claim 1. 5

3. The y8 T cell activator according to claim 1, wherein said activator is a compound of formula (m): R3 O O I 11 11 R5-N-C-C-A- -P-B- P-Y I I I I R7 R4 O-Cat+ O-Cat+ m (III) wherein Cat+, m, B, A, Rs, R 3 , R 4 , R7, and Y have the same meaning as claim 1. 10

4. The y8 T cell activator according to claim 1, wherein said activator is a compound of formula (V): R3 O O I II ii R5-W=C-C A- -- B- -P-Y I I I I CH R4 LO-Cat+ O-Cat+ - -m (V) wherein Cat+, m, B, A, W, Rs, R3, R 4 , R 6 , and Y have the same meaning as claim 1. 15 20 WO 2006/103568 PCT/IB2006/001206 54

5. The y8 T cell activator according to claim 1, wherein said activator is a compound of formula (IV): R3 0 0 HOCH-W= C-C-A- -P-B- -P-Y I I II II R7 R4 O-Cat+ O-Cat+ - - m (IV) wherein Cat+, m, B, A, W, Rs, R 3 , R 4 , R 6 , R7, and Y have the same meaning as claim 1. 5

6. The y5 T cell activator according to claim 4 or 5, wherein said activator is a compound of formula (VI): R3 O O HOCH 2 W=C-C-A P-B -Y I I I i CH 3 R4 O-Cat+ O-Cat+ m (VI) wherein Cat+, m, B, A, W, R3, R 4 , R 6 , and Y have the same meaning as claim 1. 10

7. The y3 T cell activator according to any one of claims 1 to 3, wherein R5 is -CH 2 -OH, -CHO, CO-CH 3 or -CO-OCH 3 .

8. The y8 T cell activator according to claim 7, wherein R5 is -CH 2 -OH. 15

9. The y6 T cell activator according to any one of claims 1 to 3, 7 and 8, wherein R7 is CH 3 or an isosteric group thereof, such as CH 2 F, CF 2 H or CF 3 .

10. The y8 T cell activator according to claim 9, wherein R7 is CH 3 . 20

11. The y8 T cell activator according to any one of claims 1 to 10, wherein A is O.

12. The y8 T cell activator according to any one of claims 1 to 10, wherein A is NH. 25

13. The yS T cell activator according to any one of claims 1 to 10, wherein A is CHF, CF 2 or CH 2 . WO 2006/103568 PCT/IB2006/001206 55

14. The y8 T cell activator according to any one of claims 1 to 13, wherein B is O.

15. The y8 T cell activator according to any one of claims 1 to 14, wherein m is 1. 5

16. The 78 T cell activator according to any one of claims 1 to 15, wherein Y is O'Cat+ or a nucleoside, preferably O-Cat+.

17. The y8 T cell activator according to claim 5, wherein said activator is is a compound of formula (XII): OH 0 0 OOI O-P--P-O'Cat* I -I 10 O-Cat+ O-Cat (XII)

18. The y38 T cell activator according to claim 5, wherein said activator is is a compound of formula (XIII) OH 0 0 OOI P-O-P-O'Cat* I I + O-Cat+ O-Cat (XIII) 15

19. The y8 T cell activator according to claim 5, wherein said activator is a compound of formula (XIV) : OH II N-P-O-P0O-Cat* H" I I O-Cat O-Cat (XIV) 20

20. A pharmaceutical composition comprising a 78 T cell activator according to any one of claims 1-19.

21. A y 5 T cell activator according to any one of claims 1-19 as a medicament. WO 2006/103568 PCT/IB2006/001206 56

22. Use of a y8 T cell activator according to any one of claims 1-19 for the manufacture of a pharmaceutical composition for regulating y8 T cells in a human subject.

23. Use of a y8 T cell activator according to any one of claims 1-19 for the manufacture of a 5 pharmaceutical composition for treating a subject suffering from or susceptible to suffering from a cancer, an infectious disease, an autoimmune disease or an allergic disease.

24. Use according to claim 13, wherein said cancer is a solid tumor. 10

25. Use of a y8 T cell activator according to any one of claims 1-19 as a vaccine adjuvant.

26. A vaccine composition comprising a y8 T cell activator according to any one of claims 1-19 as a vaccine adjuvant. 15

27. A method of activation a y8 T cell, the method comprising bringing a y8 T cell into contact with a y8 T cell activator according to any one of claims 1-19.

28. The method of claim 27 wherein the y8 T cell is brought into contact with said y8 T cell activator in vitro. 20

29. A y8 T cell activated according to a method of claims 27 or 28.

30. Use of a y8 T cell according to claim 29 for the manufacture of a pharmaceutical composition.